Breast and prostate cancer treatment method

ABSTRACT

The invention provides methods to treating conditions such as prostate cancer, or for ameliorating one or more symptoms associated with prostate cancer, or for agents that modulate the biological activity of the androgen receptor. The invention also provides methods and compositions suitable for therapeutic applications.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of abandoned U.S.application Ser. No. 09/675,323, filed Sep. 28, 2000, which claimspriority of U.S. provisional application Ser. No. 60/157,275, filed Sep.30, 1999, U.S. provisional application Ser. No. 60/157,347, filed Sep.30, 1999, and U.S. provisional application Ser. No. 60/166,116, filedNov. 16, 1999, all of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

The invention provides methods and compositions comprising steroids oranalogs, such as analogs of androst-5-ene-3β,17β-diol (“AED”) or1,3,5(10)-estratriene-17α-ethynyl-3β,17β-diol (“EED”) for use as agentsto modulate the biological activity of the androgen receptor (“AR”) orto treat androgen responsive or related conditions such as prostatecancer and benign prostatic hypertrophy (“BPH”).

Prostate cancer represents the most commonly diagnosed non-cutaneousmalignancy in aging males and is the second leading cause ofcancer-related death in North American men. Androgen ablation has beenthe cornerstone of treatment for advanced forms of this disease,typically by a combination of surgical or medical antiandrogen therapy.Antiandrogens that are commonly used include hydroxyflutamide (HF),cyproterone acetate and bicalutamide (casodex). Androgen ablationtreatments are used to reduce the level of endogenous androgens.However, most androgen-dependent prostate cancer cases appear toprogress to androgen-independent malignancies. Limiting the availabilityof androgens to regional or metastatic prostate cancers usually inducesremission, but after some time the cancer often becomes refractory toandrogen ablation treatments. It has been suggested that genetic changesof the AR gene may contribute to a short response to anti-androgentherapy. However, the mechanisms responsible for conversion of prostatecancer cells to an androgen independent condition are not fullycharacterized.

BPH is a disease that affects approximately 60% of males older thanabout 60 years of age. An elevated accumulation of male hormones such asdihydrotestosterone (“DHT”) in prostate tissue may contribute toprostate enlargement. The accumulation of DHT appears to result fromelevated intracellular DHT receptor levels. The increase is associatedwith an elevation of estrogen levels relative to androgen levels, whichdecrease with age. The urological symptoms consist in an elevatedfrequency of miction due to elevated residual urine. This is typicallyaccompanied by a weak flow of urine, a time-delayed start of miction,and repeated infections of the bladder and kidneys. BPH treatmentincludes surgery to remove the obstruction, but this is not alwayseffective or has unwanted side-effects, e.g., incontinence or decreasedlibido. Other treatments such as androgen ablation by bilateralorchiectomy or androgen ablation chemotherapy are too invasive or haveunwanted side-effects. Less invasive methods exist, e.g. balloondilatation. treatment with hyperthermia or microwaves, but they can havelimited efficacy.

Chemotherapy for conditions such as prostate cancer and BPH, or theirsymptoms, include administering androgen synthesis inhibitors such as 5αreductase inhibitors to inhibit production of sex hormones such astestosterone or dihydrotestosterone, or administering Naftopidil fordysuria. Treatment with 5α reductase inhibitors has been combined withother treatments such as anti-estrogens, aromatase (estrogen synthetase)inhibitors, inhibitors of 17β-hydroxysteroid dehydrogenase orluteinizinq hormone releasing hormone agonists or antagonists. Otherproposed treatments include administering aromatase inhibitors such as4-hydroxyandrostene-3,17-dione. Chemotherapy typically has drawbacks. Itcan have unwanted side effects, particularly in older patients or it canbecome ineffective over time. Various treatments and their limitationshave been described, see, e.g., U.S. Pat. Nos. 4,059,630, 4,310,523,4,659,695, 4,970,204, 5,137,882, 5,372,996, 5,494,914, 5,561,124,5,593,981, 5,994,334, 5,994,335, 5,998,377, 6,015,806, 6,093,722,6,110,906 and European publication EP 0 401 653.

Biological properties of AED and related steroid compounds have beendisclosed, see, e.g., U.S. Pat. Nos. 2,833,793, 2,911,418, 3,148,198,3,471,480, 3,710,795, 3,711,606 3,976,691, 4,268,441, 4,427,649,4,542,129, 4,666,898, 4,898,694, 4,956,355, 4,978,532, 5,001,119,5,043,165, 5,077,284, 5,028,631, 5,110,810, 5,157,031, 5,162,198,5,175,154, 5,206,008, 5,277,907, 5,292,730, 5,296,481, 5,372,996,5,387,583, 5,407,684, 5,424,463, 5,461,042, 5,478,566, 5,506,223,5,518,725, 5,527,788, 5,527,789, 5,532,230, 5,559,107, 5,562,910,5,583,126, 5,585,371, 5,587,369, 5,591,736, 5,593,981, 5,610,150,5,635,496, 5,641,766, 5,641,768, 5,656,621, 5,660,835, 5,677,366,5,686,438, 5,696,106, 5,700,793, 5,707,983, 5,709,878, 5,710,143,5,714,481, 5,728,688, 5,736,537, 5,744,462, 5,753,237, 5,756,482,5,776,921, 5,776,923, 5,780,460, 5,795,880, 5,798,347, 5,798,348,5,804,576, 5,807,848, 5,807,849, 5,811,418, 5,824,313, 5,824,668,5,824,671, 5,827,841, 5,837,269, 5,837,700, 5,843,932, 5,846,963,5,856,340, 5,859,000, 5,869,090, 5,863,910, 5,872,114, 5,872,147 and5,910,407; German patent numbers 2035738 and 2705917; PCT publicationnumbers WO 95/21617, WO 97/48367, WO 98/05338, WO 98/50040, WO 98/50041,WO 98/58650; European publication number 0020029.

The androgen receptor and co-activators such as ARA₇₀, ARA₂₄, ARA₅₄,ARA₅₅ and Rb, and methods to use them have been described, e.g., U.S.Pat. Nos. 5,789,170, 5,614,620; International publication number WO00/04152.

The invention methods and compositions accomplish one or more of severalobjects. Invention objects include providing methods and compositions toinhibit proliferation of prostate cancer cells a subject. Other objectsare to provide methods to make and use compositions and formulationscomprising EED analogs or other compounds disclosed herein. Additionalobjects will be apparent from the disclosure.

SUMMARY OF THE INVENTION

In accordance with the objects, the invention provides a method to treator prevent an androgen responsive disease such as prostate cancer,benign prostatic hyperplasia or breast cancer in a subject, or toameliorate one or more symptoms thereof, comprising administering to asubject, or delivering to the subject's tissues, an effective amount ofa compound of formula 1 or 2

wherein, R¹-R²⁸ independently are —H, —OR^(PR), —SR^(PR), —N(R^(PR))₂,—O—Si—(R^(A))₃, —CN, —NO₂, —OSO₃H, —OPO₃H, an ester, a phosphoester, aphosphonoester, a sulfite ester, a sulfate ester, an amide, an aminoacid, a peptide, an ether, a thioether, an acyl group, a carbonate, acarbamate, a slufonamide, a halogen, an optionally substituted alkylgroup, an optionally substituted alkenyl group, an optionallysubstituted alkynyl group, an optionally substituted aryl moiety, anoptionally substituted heterocycle, an optionally substituted heteroarylmoiety, an optionally substituted monosaccharide, an optionallysubstituted oligosaccharide, a nucleoside, a nucleotide, anoligonucleotide, a polymer, or, when two of R¹-R²⁸ are linked to thesame carbon atom (e.g., R⁵ and R⁶ or R¹² and R¹³), they independentlycomprise a double bond, such as ═O, ═S, ═CH₂ or ═N—OH, at one or morering carbons, and provided that when one or more of the rings comprisesa double bond, one of the variable groups that is bonded to the doublebonded ring carbon is absent; each R^(A) independently is C₁₋₈ alkyl;each R^(PR) independently is —H or a protecting group; and the dottedlines are optional double bonds, provided that 2, 3, 4 or more of R¹-R²⁸are not hydrogen, and provided that compound is not17α-ethynyl-17β-hydroxy-4-estrene-3-one,17α-ethynyl-17β-hydroxy-5(10)-estrene-3-one,1,3,5(10)-estratriene-17β-ethynyl-3β,17β-diol,17α-ethynyl-androst-5-ene-3β,17β-diol,17α-ethynyl-17β-hydroxy-4-androsten-3-one,3β,17β-dihydroxy-androst-5-en-16-one, 3β,17β-dihydroxy-androst-4-en,3β,-methylcarbonate-androst-5-en-7,17-dione,3β,17β-dihydroxy-androst-5-en-11-one,3β,17β-diacetoxy-androst-5-ene-7α,17β-diol,3β,17β-diacetoxy-androst-5-ene-7-one,3β-methoxy-androst-5-ene-7α,17β-diol,17β-methoxy-androst-3,5-diene-7-one,17β-hydroxy-androst-3,5-diene-7-one, 5α-androstane-3α,17β-diol or anester, ether or salt of any of these compounds.

Other objects will become apparent on reading the disclosure.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 The effects of various DHEA metabolites on the transcriptionalactivity of AR.

FIG. 2 The structures of DHEA derivatives and effects on theAdiol-induced AR transcriptional activity. (A) The structures ofcompounds No. 4, 6, 8 & 10, DHEA, Adiol, and testosterone. (B) CATactivity determined in PC-3 cells transiently co-transfected with WtARand MMTV-CAT.

FIG. 3 The suppression effects of No. 4, 6, 8 & 10 DHEA derivatives onthe DHT induced AR transcriptional activity.

FIG. 4 The effects No. 4, 6, 8 & 10 DHEA derivatives on theAdiol-induced and HF-blocked AR transcriptional activity.

FIG. 5 The effects No. 4, 6, 8 & 10 DHEA derivatives on the ER, PR, orGR transcriptional activity.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and unless otherwise stated or implied by context, thefollowing terms have the meanings defined here.

A “subject” means a human or animal. Usually the animal is a vertebratesuch as a primate, rodent, domestic animal or game animal. Primatesinclude chimpanzees, cynomolqus monkeys, spider monkeys, and macaques,e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbitsand hamsters. Domestic and game animals include cows, horses, pigs,deer, bison, buffalo, felines, e.g., domestic cat, dogs, e.g., domesticdog, wolf, birds, e.g., chicken, turkey, emu, ostrich, and fish, e.g.,trout, catfish and salmon. Subject includes any subset of the foregoing,e.g., all of the above, but excluding one or more groups or species suchas humans, primates or rodents.

Expressions that refer to “a formula 1 compound”, “a compound of formula1”, “a formula 2 compound” or the like means compounds, compositions orformulations where one or more than one formula 1 (or formula 2)compound is present, typically 1, 2, 3 or 4, usually 1.

A “mimetic of a formula 1 or 2 compound” or a “mimetic of EED” means anycompound, steroid or non-steroid (e.g., a compound disclosed in one ormore of the references cited herein), that qualitatively orquantitatively induces the same or similar biological responses to anysignificant degree that one or more formula 1 compounds or EED induces.Biological responses include modulation of AR-mediated transcription orinhibition of replication of cells, e.g., prostate cancer cells. Ingeneral, a mimetic of a formula 1 or 2 compound, e.g. EED, will induceat least about 35%, preferably at least about 50%, of the biologicalresponse that the formula 1 or 2 compound induces as optionally comparedto suitably controlled and untreated reference cells, cell populations(in vitro or in vivo) or subjects. Typically the biological responsewill be defined by measuring one, two, three or more parameters, e.g.,modulation of the synthesis of one or more gene products or modulationof cell replication.

“Alkyl” as used here means linked normal, secondary, tertiary or cycliccarbon atoms, i.e., linear, branched or cyclic. The number of carbonatoms in an alkyl group or moiety is 1 to about 20, unless otherwisespecified, e.g., C₁₋₈ alkyl means an alkyl moiety containing 1, 2, 3, 4,5, 6, 7 or 8 carbon atoms. Examples include methyl, ethyl, 1-propyl(n-propyl), 2-propyl (i-propyl, —CH(CH₃)₂), 1-butyl (n-butyl),2-methyl-1-propyl (i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂),2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂),3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl, 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃), cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

“Alkenyl” means linked normal, secondary, tertiary or cyclic carbonatoms where one or more double bonds (e.g., —CH═CH—) are present,typically 1, 2 or 3, usually 1 or 2. The number of carbon atoms in analkenyl group or moiety is 2 to about 20, unless otherwise specified,e.g., C₂₋₈ alkenyl means an alkenyl moiety containing 2, 3, 4, 5, 6, 7or 8 carbon atoms.

“Alkynyl” means linked normal, secondary, tertiary or cyclic carbonatoms where one or more triple bonds (—C≡C—) are present, typically 1, 2or 3, usually 1. The number of carbon atoms in an alkynyl group ormoiety is 2 to about 20, unless otherwise specified, e.g., C₂₋₈ alkynylmeans an alkynyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

“Aryl” means phenyl or naphthyl.

“Aryl-alkyl”, aryl-alkenyl” and aryl-alkynyl” respectively mean an arylmoiety bonded to an alkyl, alkenyl or alkynyl group, wherein aryl,alkyl, alkenyl and alkynyl have the meanings defined above. Exemplaryaryl-alkyl moieties have the structure aryl-C₁₋₂₀ alkyl- or aryl-C₂₋₂₀alkenyl-, e.g., aryl-CH₂—, phenyl-CH₂—, phenyl-CH₂—CH═CH—CH₂—. Typicallythe alkyl groups will comprise 1-8 carbon atoms that are linear orbranched and typical alkenyl and alkynyl groups will comprise 1-8 carbonatoms that are linear or branched.

“Substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”“substituted aryl-alkyl”, “substituted aryl-alkenyl” and “substitutedaryl-alkynyl” mean an alkyl, alkenyl, alkynyl, aryl-alkyl, aryl-alkenylor aryl-alkynyl group respectively, that comprises 1, 2, 3 or moreindependently selected substituents bonded to a carbon atom or 1, 2, 3or more independently selected substituents that replace or interruptany carbon atom chain or ring. Substituents include ethers (—O—),ketones (—C(O)—), —OR^(PR) (including —OH), —C(O)OR^(PR) (including—C(O)OH), —C(O)O—, —C(S)OR^(PR), —C(S)O—, —OC(O)—, —C(O)H, —OCH₂—,—OCH₂CH₂—, —OCH₂O—, —OCH₂CH₂O—, —NR^(PR)—, —N(R^(PR))₂, —NHR^(PR),—NHC(O)—, —CH₂—NR^(PR)—, —CH₂—NHR^(PR), —CH₂—NHC(O)—, —C(O)NH—,—C(O)NHR^(PR), —OC(O)NR^(PR)—, —OC(O)NHR^(PR), —NR^(PR)C(O)NR^(PR)—,—NR^(PR)C(O)NHR^(PR), —NR^(PR)CH₂—, —NR^(PR)CH₂CH₂—, —S—, —SR^(PR),—S(O)—, —S(O)(O)—, —S(O)OR^(PR), —S(O)H, —CN, —NO₂,—O—CH₂—O—C(O)—OR^(PR) (including —O—CH₂—O—C(O)—OH),—O—CH₂—O—C(O)—SR^(PR) (including —O—CH₂—O—C(O)—SH), —O—CH₂—C(O)—NHR^(PR)(including —O—CH₂—C(O)—NH₂), —O—CH₂—C(O)—R^(PR) (including—O—CH₂—C(O)—OH), —O—CH₂—C(O)—SR^(PR) (including —O—CH₂—C(O)—SH),—O—CH₂—OR^(PR) (including —O—CH₂—OH), —O—CH₂—CH₂—OR^(PR) (including—O—CH₂—CH₂—OH), —O—CH₂—CH₂—O—CH₂—CH₂—OR^(PR) (including—O—CH₂—CH₂—OCH₂—CH₂—OH), halogen, and combinations of these moietieswhere R^(PR) independently is hydrogen, a protecting group or bothR^(PR) together are a protecting group. In some embodiments, alkenyl,alkynyl, aryl-alkenyl and aryl-alkynyl groups comprise one, two, threeor more substituents, and such substituents are optionally bonded to acarbon atom that is one or more methylene moiety removed from the doublebond, i.e., the substituent is separated at least by 1, 2, 3 or more—CH₂— moieties from a double bond.

Heterocycle. “Heterocycle” or “heterocyclic” includes by way of exampleand not limitation these heterocycles described in Paquette, Leo A.;“Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York,1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry ofHeterocyclic Compounds, A series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. 1960, 82:5566.

Examples of heterocycles include by way of example and not limitationpyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidizedtetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl,6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl,pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,and isatinoyl.

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Typically, nitrogen bonded heterocyclesinclude 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl,and 1-piperidinyl.

“Heteroaryl” or “heteroaromatic” means an aromatic ring or two or morefused rings that contain one or more aromatic rings where the ring orfused rings comprise 1, 2, 3 or more heteroatoms, usually oxygen (—O—),nitrogen (—NR^(PR)—) or sulfur (—S—) where R^(PR) is —H, a protectinggroup, optionally substituted C₁₋₈ alkyl, optionally substituted C₂₋₈alkenyl or optionally substituted C₂₋₈ alkynyl, usually —H. Examples areas described for heterocycle and heteroaryl or heteroaromatic groupscomprise a subset of heterocycles.

“Alcohol” as used herein means an alcohol that comprises a C₁₋₂₀ alkylmoiety substituted at one, two or more hydrogen atoms with one, two ormore hydroxyl groups. Alcohols include ethanol, n-propanol, i-propanol,n-butanol, i-butanol, s-butanol, t-butanol, n-pentanol, i-pentanol,n-hexanol, cyclohexanol, n-heptanol, n-octanol, n-nonanol, n-decanol,ethylene glycol and glycerol. The carbon atoms in alcohols can bestraight, branched or cyclic. Alcohol includes any subset of theforegoing, e.g., C₁₋₆ alcohols (alcohols having 1, 2, 3, 4, 5 or 6carbon atoms).

“Halogen” means fluorine, chlorine, bromine or iodine.

“Protecting group” or “R^(PR)” means a moiety that prevents the atom towhich it is linked from participating in unwanted reactions, or itlimits such reactions. For example, for —OR^(PR), R^(PR) may be hydrogenor a protecting group for the oxygen atom found in a hydroxyl. For—C(O)—OR^(PR), R^(PR) may be hydrogen or a carboxyl protecting group,for —SR^(PR), R^(PR) may be hydrogen or a protecting group for sulfur inthiols for instance, and for —NHR^(PR) or —N(R^(PR))₂-, R^(PR) may behydrogen or a nitrogen atom protecting group for primary or secondaryamines. One or more hydroxyl, thiol, amine or other reactive groups maybe found in formula 1 or formula 2 compounds. These groups may requireprotection against reactions taking place elsewhere in the molecule. Theprotecting groups for oxygen, sulfur or nitrogen atoms, or for reactivegroups containing heteroatoms, are used, for example, to preventunwanted reactions with electrophilic compounds, such as acylating used,e.g., in steroid chemistry.

“Protecting groups” as used herein comprise noncyclic or cyclicprotecting groups, which have been extensively described, e.g.,“Protective Groups in Organic Chemistry”, Theodora W. Greene (John Wiley& Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (hereafter “Greene”)and will not be detailed here. The corresponding cleavage reactions havealso been described, e.g., Greene. In the context of the presentinvention, these protecting groups are groups that can be removed fromthe molecule of the invention without irreversibly changing the covalentbond structure or oxidation/reduction state of the remainder of themolecule. For example, when —R^(PR) is a removable protecting group thatis bonded to a —O— or —NH— group, it is removed to form —OH or —NH₂,respectively, without affecting other covalent bonds in the molecule. Insome embodiments, the protecting group will not be removable withoutaffecting other covalent bonds in the molecule. More than one protectinggroup can be removed at a time, or they can be removed sequentially. Theformula 1 or 2 compounds may contain one or more than one protectinggroup, which may be the same or different.

Removable protecting groups are usually removed by known procedures,although it will be understood that the protected intermediates fallwithin the scope of this invention. The removal of the protecting groupmay require several steps or removal may be straight-forward, dependingupon the economics and nature of the conversions involved. In general,one will use a protecting group with exocyclic amines or with carboxylgroups during synthesis of a formula 1 or 2 compound. For mosttherapeutic applications protected groups will be deprotected, unlessthe protecting group is one that can be removed under physiologicalconditions. Protecting groups commonly are employed to protect againstcovalent modification of a sensitive group in reactions such asalkylation or acylation. Ordinarily, protecting groups are removed by,e.g. hydrolysis, elimination or aminolysis. Thus, simple functionalconsiderations will suffice to guide the selection of a reversible or anirreversible protecting group at a given locus on the inventioncompounds. Suitable protecting groups and criteria for their selectionare described in T. W. Greene and P. G. M. Wuts, Eds. “Protective Groupsin Organic Synthesis” 2nd edition, Wiley Press, at pps. 10-142, 143-174,175-223, 224-276, 277-308, 309-405 and 406-454.

Determination of whether a group is a protecting group is made in theconventional manner, e.g., as illustrated by Kocienski, Philip J.;“Protecting Groups” (Georg Thieme Verlag Stuttgart, New York, 1994)(hereafter “Kocienski”), Section 1.1, page 2, and Greene Chapter 1,pages 1-9. In particular, a group is a protecting group if when, basedon mole ratio, 90% of that protecting group has been removed by adeprotection reaction, no more than 50%, preferably no more than 25%,more preferably no more than 10%, of the deprotected product moleculeshave undergone changes to their covalent bond structure oroxidation/reduction state other than those occasioned by the removal ofthe protecting group. When multiple protecting groups of the same typeare present in the molecule, the mole ratios are determined when all ofthe groups of that type are removed. When multiple protecting groups ofdifferent types are present in the molecule, each type of protectinggroup is treated (and the mole ratios are determined) independently ortogether with others depending on whether the deprotection reactionconditions pertinent to one type are also pertinent to the other typespresent. In one embodiment of the invention, a group is a protectinggroup if when, based on mole ratio determined by conventionaltechniques, 90% of that protecting group has been removed by aconventional deprotection reaction, no more than 50%, preferably 25%,more preferably 10%, of the deprotected product molecules of theinvention have undergone irreversible changes to their covalent bondstructure or oxidation/reduction state other than those occasioned bythe removal of the protecting group. Irreversible changes requirechemical reactions (beyond those resulting from aqueous hydrolysis,acid/base neutralization or conventional separation, isolation orpurification) to restore the covalent bond structure oroxidation/reduction state of the deprotected molecule of the invention.

“Ester” means a moiety that comprises a —C(O)—O— structure. Typically,esters as used here, comprise an organic moiety containing about 1-50carbon atoms, usually about 2-18 carbon atoms, and 0 to about 10independently selected heteroatoms (e.g., O, S, N, P, Si, F, Cl, Br, I),usually about 1-6 heteroatoms, linked to a formula 1 or formula 2steroid nucleus at 1, 2, 3, 4 or more of R¹-R²⁸ through the —C(O)—O—structure, e.g., organic moiety-C(O)—O-steroid or organicmoiety-O—C(O)-steroid. When more than one ester is present, e.g., 2, 3or 4 esters, each ester moiety is independently selected. The organicmoiety usually comprises one or more of any of the organic groupsdescribed above, e.g., C₁₋₂₀ alkyl moieties, C₂₋₂₀ alkenyl moieties,C₂₋₂₀ alkynyl moieties, aryl moieties, C₂₋₉ heterocycles, an estermoiety or substituted derivatives of any of these. Typical substitutionsfor these organic groups include 1, 2, 3, 4 or more, usually 1 or 2independently selected, —O—, —S—, —NR^(PR)—, —C(O)—, —N(R^(PR))₂,—C(O)OR^(PR), —OC(O)R^(PR), —OR^(PR), βSR^(PR), —NO₂, ═O, ═S, —CN,—NHC(O)—, —C(O)NH—, —OC(O)—, —C(O)O—, —O-A8, —S-A8, —C(O)-A8, —OC(O)-A8,—C(O)O-A8, ═N—, —N═, —OPO₃(R^(PR))₂, —OSO₃H₂ or halogen moieties oratoms, where R^(PR) independently is —H, a protecting group or bothR^(PR) together are a protecting group and A8 is C₁₋₈ alkyl, C₁₋₈alkenyl, C₁₋₈ alkynyl, C₁₋₆ alkyl-C₂₋₉ aryl (e.g., benzyl), aryl (e.g.phenyl) or C₀₋₆ alkyl-C₁₋₇ heterocycle. Substitutions are independentlychosen. The organic moieties exclude obviously unstable moieties, e.g.,—O—O—, except where such unstable moieties are transient species thatone can use to make a compound with sufficient chemical stability forthe one or more of the uses described herein. The substitutions listedabove are typically substituents that one can use to replace a one ormore carbon atoms, e.g., —O— or —C(O)—, or one or more hydrogen atom,e.g., halogen, —NH₂ or —OH. In some embodiments, the ester isunsubstituted, i.e., H—C(O)—O-steroid.

“Thioester” means a moiety that comprises a —C(S)—O— structure.Typically, thioesters as used here comprise a hydrogen atom or anorganic moiety containing about 1-50 carbon atoms and 0 to about 10independently selected heteroatoms (e.g., O, S, N, P, Si) linked to aformula 1 or 2 steroid nucleus at 1, 2, 3, 4 or more of R¹-R²⁸ throughthe —C(S)—O— structure, e.g., organic moiety-C(S)—O-steroid or organicmoiety-O—C(S)-steroid. The organic moiety is as described above foresters. In some embodiments, the thioester is unsubstituted, i.e.,H—C(S)—O-steroid.

“Phosphoester” or “phosphate ester” means a moiety that comprises a—O—P(OR^(PR))(O)—O— structure where R^(PR) is hydrogen (—H), aprotecting group or an organic moiety as described for esters.Typically, phosphoesters as used here comprise a hydrogen atom, aprotecting group or an organic moiety containing about 1-50 carbon atomsand 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P,Si) linked to a formula 1 or 2 steroid nucleus at 1, 2, 3, 4 or more ofR¹-R²⁸ through the —O—P(OR^(PR))(O)—O— structure, i.e., organicmoiety-O—P(OR^(PR))(O)—O— steroid. The organic moiety is as describedabove for esters. In some embodiments, the phosphate ester isunsubstituted, e.g., HO—P(OR^(PR))(O)—O-steroid.

“Phosphonoester” means a moiety that comprises 1, 2, 3, 4 or more,typically only 1, —P(OR^(PR))(O)—O— structure where R^(PR) is —H, aprotecting group or an organic moiety as described for esters.Typically, phosphonoesters as used here comprise a hydrogen atom, aprotecting group or an organic moiety containing about 1-50 carbon atomsand 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P,Si) linked to a formula 1 or 2 steroid nucleus at 1, 2, 3, 4 or more ofR¹-R²⁸ through the —P(OR^(PR))(O)—O— structure, i.e., organicmoiety-P(OR^(PR))(O)—O-steroid or steroid-P(OR^(PR))(O)—O-organicmoiety. The organic moiety is as described above for esters. In someembodiments, the phosphonoester is unsubstituted, e.g.,H—P(OR^(PR))(O)—O-steroid.

“Sulfate ester” means a moiety that comprises 1, 2, 3, 4 or more—O—S(O)(O)—O-structure, usually 1. Typically, sulfate esters as usedhere comprise a hydrogen atom, a protecting group or an organic moietycontaining about 1-50 carbon atoms and 0 to about 10 independentlyselected heteroatoms (e.g., O, S, N, P, Si) linked to a formula 1 or 2steroid nucleus at 1, 2, 3, 4 or more of R¹-R²⁸ through the—O—S(O)(O)—O— structure, e.g., organic moiety-O—S(O)(O)—O-steroid. Theorganic moiety is as described above for esters. In some embodiments,the sulfate ester is unsubstituted, i.e., HO—S(O)(O)—O-steroid.

“Sulfite ester” means a moiety that comprises 1, 2, 3, 4 or more—O—S(O)—O-structures, usually 1. Typically, sulfite esters as used herecomprise an organic moiety containing about 1-50 carbon atoms and 0 toabout 10 independently selected heteroatoms (e.g., O, S, N, P, Si)linked to a formula 1 or 2 steroid nucleus at 1, 2, 3, 4 or more ofR¹-R²⁸ through the —O—S(O)—O— structure, e.g., organicmoiety-O—S(O)—O-steroid. The organic moiety is as described above foresters. In some embodiments, the sulfite ester is unsubstituted, i.e.,HO—S(O)—O-steroid.

“Sulfonamide” means a moiety that comprises 1, 2, 3, 4 or more—S(O)(O)—N(R^(A))(R^(B)) or —S(O)(O)—N(R^(A))— structures, usually 1,where R^(A) and R^(B) independently are —H, a protecting group, anorganic moiety (as described for esters), or both R^(A) and R^(B)together comprise a protecting group. Typically, sulfonamides as usedhere comprise an organic moiety containing about 1-50 carbon atoms and 0to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si)linked to a formula 1 or 2 steroid nucleus at 1, 2, 3, 4 or more ofR¹-R²⁸ through the —O—S(O)—O— structure, e.g., organicmoiety-S(O)(O)—NH-steroid or N(R^(A))(R^(B))—S(O)(O)-steroid. Theorganic moieties are as described above for esters, e.g., moieties thatcomprise 1 to about 22 carbon atoms and up to about 10 independentlyselected heteroatoms. In some embodiments, the sulfonamide isunsubstituted, e.g., H₂N—S(O)(O)-steroid.

“Amide” means an organic moiety as described for ester that comprises 1,2, 3, 4 or more —C(O)NR^(PR)— moieties, usually 1 or 2, where R^(PR) is—H or a protecting group, R^(PR) is usually H. In some embodiments, the—C(O)NR^(PR)— group is linked to the steroid nucleus at 1, 2, 3, 4 ormore of R¹-R²⁸ through the —NR^(PR)— moiety, e.g., organicmoiety-C(O)—NR^(PR)-steroid or steroid-C(O)—NR^(PR)-organic moiety. Theorganic moiety is as described above for esters. In some embodiments,the amide is unsubstituted, i.e., H₂N—C(O)-steroid or HC(O)—NH-steroid.

“Ether” means an organic moiety as described for ester that comprises 1,2, 3, 4 or more —O— moieties, usually 1 or 2. In some embodiments, the—O— group is linked to the steroid nucleus at 1, 2, 3, 4 or more ofR¹-R²⁸ through the —O— moiety, e.g., organic moiety-O-steroid. Theorganic moiety is as described above for esters.

“Thioether” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —S— moieties, usually 1 or 2. In someembodiments, the —S— group is linked to the steroid nucleus at 1, 2, 3,4 or more of R¹-R²⁸ through the —S— moiety, e.g., organicmoiety-5-steroid. The organic moiety is as described above for esters.

“Acyl group” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —C(O)— groups. In some embodiments, the—C(O)— group is linked to the steroid nucleus at 1, 2, 3, 4 or more ofR¹-R²⁸, e.g., organic moiety-C(O)-steroid. The organic moiety is asdescribed above for esters. An unsubstituted acyl group comprises aHC(O)— moiety, e.g., linked to the steroid nucleus.

“Carbonate” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —O—C(O)—O— structures. Typically, carbonategroups as used here comprise an organic moiety containing about 1-50carbon atoms and 0 to about 10 independently selected heteroatoms (e.g.,O, S, N, P, Si) linked to a formula 1 or formula 2 steroid nucleus at 1,2, 3, 4 or more of R¹-R²⁸ through the —O—C(O)—O-structure, e.g., organicmoiety-O—C(O)—O-steroid. The organic moiety is as described above foresters. An unsubstituted carbonate group comprises a HO—C(O)—O-moiety,e.g., linked to the steroid nucleus.

“Carbamate” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —O—C(O)NR^(PR)— structures where R^(PR) is—H, a protecting group or an organic moiety as described for ester.Typically, carbamate groups as used here comprise an organic moietycontaining about 1-50 carbon atoms and 0 to about 10 independentlyselected heteroatoms (e.g., O, S, N, P, Si) linked to a formula 1 orformula 2 steroid nucleus at one or more of R¹-R²⁸ through the—O—C(O)—NR^(PR)-structure, e.g., organic moiety-O—C(O)—NR^(PR)-steroidor steroid-O—C(O)—NR^(PR)-organic moiety. The organic moiety is asdescribed above for esters. An unsubstituted carbamate group comprises aHO—C(O)—NH— or H₂N—C(O)—O— moiety, e.g., linked to the steroid nucleus.

As used herein, “monosaccharide” means a polyhydroxy aldehyde or ketonehaving the empirical formula (CH₂O)_(n) where n is 3, 4, 5, 6 or 7.Monosaccharide includes open chain and closed chain forms, but willusually be closed chain forms. Monosaccharide includes hexofuranose andpentofuranose sugars such as 2′-deoxyribose, ribose, arabinose, xylose,their 2′-deoxy and 3′-deoxy derivatives and their 2′,3′-dideoxyderivatives. Monosaccharide also includes the 2′,3′ dideoxydidehydroderivative of ribose. Monosaccharides include the D-, L- and DL-isomersof glucose, fructose, mannose, idose, galactose, allose, gulose,altrose, talose, fucose, erythrose, threose, lyxose, erythrulose,ribulose, xylulose, ribose, arabinose, xylose, psicose, sorbose,tagatose, glyceraldehyde, dihydroxyacetone and their monodeoxyderivatives such as rhamnose. Monosaccharides are optionally protectedor partially protected. The formula 1 and formula 2 compounds maycomprise 1, 2, 3 or more independently selected monosaccharides at oneor more of R¹-R²⁸.

Disaccharide and oligosaccharide mean a moiety that comprisesrespectively two or more linked monosaccharides. Substituteddisaccharide or substituted oligosaccharide means a moiety thatcomprises two or more linked monosaccharides, at least one of which is asubstituted monosaccharide. The formula 1 and formula 2 compounds maycomprise 1, 2, 3 or more independently selected disaccharides oroligosaccharides at one or more of R¹-R².

Optionally substituted alkyl group, optionally substituted alkenylgroup, optionally substituted alkynyl group, optionally substituted arylmoiety and optionally substituted heterocycle mean substitutions ofC₁₋₂₀ alkyl moieties, C₂₋₂₀ alkenyl moieties, C₂₋₂₀ alkynyl moieties,aryl moieties, C₂₋₉ heterocycles or substituted derivatives of any ofthese. Typical substitutions for these organic groups include 1, 2, 3, 4or more, usually 1 or 2 independently chosen, —O—, —S—, —NR^(PR)—,—C(O)—, —N(R^(PR))₂, —C(O)OR^(PR), —OC(O)R^(PR), —OR^(PR) (including—OH), —SR^(PR) (including —SH), —NO₂, —CN, —NHC(O)—, —C(O)NH—, —OC(O)—,—C(O)O—, —O-A8, —S-A8, —C(O)-A8, —OC(O)-A8, —C(O)O-A8, ═N—, —N═,—OPO₂R^(PR), —OSO₃H or halogen moieties or atoms, where R^(PR)independently is —H, a protecting group or both R^(PR) together are aprotecting group and A8 is C₁₋₈ alkyl, C₁₋₈ alkenyl, C₁₋₈ alkynyl, C₁₋₄alkyl-aryl (e.g., benzyl), aryl (e.g. phenyl) or C₁₋₄ alkyl-C₁₋₅heterocycle. Substitutions are independently chosen. The organicmoieties as described here, and for other any other moieties describedherein, exclude obviously unstable moieties, e.g., —O—O—, except wheresuch unstable moieties are transient species that one can use, forexample, to make a compound with sufficient chemical stability for theone or more of the uses described herein.

Optionally substituted “monosaccharide” comprise any C3-C7 sugar, in theD-, L- or DL-configurations, e.g., erythrose, glycerol, ribose,deoxyribose, arabinose, glucose, mannose, galactose, fucose, mannose,glucosamine, N-acetylneuraminic acid, N-acetylglucosamine,N-acetylgalactosamine or glucuronic acid, that is optionally substitutedat one or more hydroxyl groups. Suitable substitutions include hydrogen,protected hydroxyl, carboxyl, azido, cyano, acetyl, —O—C₁₋₆ alkyl,—S—C₁₋₆ alkyl, —O—C₂₋₆ alkenyl, —S—C₂₋₆ alkenyl, optionally protectedamine, optionally protected carboxyl, halogen, thiol, protected thiol orsubstituents as described for substituted alkyl groups. The linkagebetween the monosaccharide the steroid is α or β.

Optionally substituted “oligosaccharide” comprises two, three, four ormore of any C3-C7 sugars that are covalently linked to each other. Thelinked sugars may have D-, L- or DL-configurations. Suitable sugars andsubstitutions are as described for monosaccharides. The linkage betweenthe oligosaccharide and the steroid is α or β, as are the linkagesbetween the monosaccharides that comprise the oligosaccharide.

Nucleoside includes 3TC, AZT, D4T, ddI, ddC, G, A, U, C, T, dG, dA, dTand dC.

Polymer includes biocompatible organic polymers, e.g., PEGs andpolyhydroxyalkyl polymers. PEG means an ethylene glycol polymer thatcontains about 20 to about 2000000 linked monomers, typically about50-1000 linked monomers, usually about 100-300. Polyethylene glycolsinclude PEGs containing various numbers of linked monomers, e.g., PEG20, PEG 30, PEG 40, PEG 60, PEG 80, PEG 100, PEG 115, PEG 200, PEG 300,PEG 400, PEG 500, PEG 600, PEG 1000, PEG 1500, PEG 2000, PEG 3350, PEG4000, PEG 4600, PEG 5000, PEG 6000, PEG 8000, PEG 11000, PEG 12000, PEG2000000 and any mixtures thereof.

Amino acid. “Amino acid” means an amino acid moiety that comprises anynaturally-occurring or synthetic amino acid residue, i.e., any moietycomprising at least one carboxyl and at least one amino residue directlylinked by one, two three or more carbon atoms, typically one (α) carbonatom. The nature and identity of the intervening structure locatedbetween the carboxyl and amino groups can have a variety of structuresincluding those described herein. Typically, amino acids linked to thesteroid through the amine group have sufficient conformation and lengthto be capable of autocatalytic hydrolysis of the amino acid-steroid bondand release of the steroid. This can occur when the free carboxyl isgenerated in vivo by deesterification, deamidation or peptidolyticcleavage of the precursor containing a linkage between the amino acid'samine group and the steroid. Hydrolysis of the bond between an aminoacid's carboxyl or amino group and the steroid can also occur bychemical or enzymatic activity, e.g., esterase cleavage or non-enzymatichydrolysis.

In general, the amino acids corresponding to the residues employed inthe invention compounds are naturally occurring and have no significantpharmacological activity per se. However, optimal pharmacokineticactivity, (substantially complete hydrolysis upon hydrolysis of thedistal amide or ester bond) may be achieved by using non-naturallyoccurring amino acid residues. The intervening structure may be assimple as methylene when the amino acid residue is glycyl, orsubstituted methylene for other α amino acids. The structure ordinarilycontains up to about 5 carbon or heteroatoms in the direct linkagebetween the amino acid's carboxyl carbon and the amine nitrogen. Thus,amino acids can comprise intervening ethylene, propylene, butylene, orpentylene groups or their substituted analogs, such as for example,oxyesters or ethers in which oxygen replaces carbon and, as appropriate,hydrogen. An example of such an intervening structure would be—CH—O—C(R²²)(R²³)—, where R²² and R²³ are independently selectedhydrogen or organic moieties as described above for esters. In someembodiments one of R²² and R²³ is hydrogen and the other is a C₂₋₂₀organic moiety. Typically the organic moieties contain about 1-20 carbonatoms and 0, 1, 2, 3, 4 or 5 independently selected heteroatoms, whichare typically selected from oxygen, nitrogen, sulfur and phosphorus. Ingeneral, fewer intervening atoms are used when more rapid hydrolysis isdesired, although larger structures are suitable if, e.g., they possesssufficient flexibility or have conformations to allow positioning of thecarboxyl group in proximity to the amino acid-steroid bond.

Ordinarily, R²² is —H, methyl or hydroxymethyl, usually —H, and R²³ is aside chain or group of a naturally occurring amino acid. Amino acid sidechains include analogs where the side chain is a C₁₋₁₅ homolog of thecorresponding natural compound, e.g., methylene, ethylene, propylene,butylene or a substituted derivative thereof, e.g., an alkyl, ether oralkoxy (e.g., methoxy, ethoxy, propoxy) substituted derivative. Ingeneral, for carboxyl-containing side chains, if the C atom of the sidechain carboxyl is linked by 5 or less atoms to the N then the carboxyloptionally will be blocked, e.g. by esterification or amidation whereinthe ester or amide bonds are hydrolyzable in vivo. R²² also is takentogether with R³⁰ to form a proline residue (—CH₂—)₃. Thus, R²³ isgenerally a side group such as —H, —CH₃, —CH(CH₃)₂, —CH₂—CH(CH₃)₂,—CHCH₃—CH₂—CH₃, —CH₂—C₆H₅, —CH₂CH₂—S—CH₃, —CH₂OH, —CH(OH)—CH₃, —CH₂—SH,—CH₂—C₆H₄OH, —CH₂—CO—NH₂, —CH₂—CH₂—CO—NH₂, —CH₂—COOH, —CH₂—CH₂—COOH,—(CH₂)₄—NH₂ and —(CH₂)₃—NH—C(NH₂)—NH₂. R²³ also includes1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl,indol-3-yl, methoxyphenyl and ethoxyphenyl. The optimal R³⁰ group isreadily selected using routine assays.

In general, the amino acid residue has the structure shown in theformulas below. Ordinarily, n is 1 or 2, R²² is —H and R²³ is a moietycontaining one or more of the following groups: amino, carboxyl, amide,carboxyl ester, hydroxyl, C₆-C₇ aryl, ether (—O—), thioether (—S—), n-,s- or t-alkyl (C₁-C₆), guanidinyl, imidazolyl, indolyl, sulfhydryl,sulfoxide, and phosphoryl. The R²² and R²³ substituents can have a widevariety of structures including those disclosed herein, e.g., esters,ethers or carbonates.

When the amino acid residues contain one or more chiral centers, any ofthe D, L, meso, threo or erythro (as appropriate) racemates or mixturesthereof, fall within the scope of this invention. In general, if it isdesired to rely on non-enzymatic means of hydrolysis, D isomers shouldbe used. On the other hand, L isomers may be more versatile since theycan be susceptible to both non-enzymatic as well as potential targetedenzymatic hydrolysis, and are more efficiently transported by amino acidor dipeptidyl transport systems in the gastrointestinal tract.

Examples of suitable amino acid residues include the following: Glycyl;aminopolycarboxylic acids, e.g., aspartic acid, β-hydroxyaspartic acid,glutamic acid, β-hydroxyglutamic acid, β-methylaspartic acid,β-methylglutamic acid, β,β-dimethylaspartic acid, γ-hydroxyglutamicacid, β,γ-dihydroxyglutamic acid, β-phenylglutamic acid,γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid,2-aminosuberic acid and 2-aminosebacic acid residues; amino acid amidessuch as glutaminyl and asparaginyl; polyamino- orpolybasic-monocarboxylic acids such as arginine, lysine, β-aminoalanine,γ-aminobutyrine, ornithine, citruline, homoarginine, homocitrulline,5-hydroxy-2,6-diaminohexanoic acid (commonly, hydroxylysine, includingallohydroxylysine) and diaminobutyric acid residues; other basic aminoacid residues such as histidinyl; diaminodicarboxylic acids such asα,α′-diaminosuccinic acid, α,α′-diaminoglutaric acid, α,α′-diaminoadipicacid, α,α′-diaminopimelic acid, α,α′-diamino-β-hydroxypimelic acid,α,α′-diaminosuberic acid, α,α′-diaminoazelaic acid, andα,α′-diaminosebacic acid residues; imino acids such as proline, 4- or3-hydroxy-2-pyrrolidinecarboxylic acid (commonly, hydroxyproline,including allohydroxyproline), γ-methylproline, pipecolic acid,5-hydroxypipecolic acid, —N([CH₂]_(n)COOR^(PR))₂, wherein n is 1, 2, 3,4, 5 or 6 and R^(PR) is —H or a protecting group, andazetidine-2-carboxylic acid residues; a mono- or di-alkyl (typicallyC₁-C₈ branched or normal) amino acid such as alanine, valine, leucine,allylglycine, butyrine, norvaline, norleucine, heptyline,α-methylserine, α-amino-α-methyl-γ-hydroxyvaleric acid,α-amino-α-methyl-δ-hydroxyvaleric acid,α-amino-α-methyl-ε-hydroxycaproic acid, isovaline, α-methylglutamicacid, α-aminoisobutyric acid, α-aminodiethylacetic acid,α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid,α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid,α-aminoethylisopropylacetic acid, α-amino-n-propylacetic acid,α-aminodiisoamyacetic acid, α-methylaspartic acid, α-methylglutamicacid, 1-aminocyclopropane-1-carboxylic acid; isoleucine, alloisoleucine,tert-leucine, β-methyltryptophan and α-amino-β-ethyl-β-phenylpropionicacid residues; β-phenylserinyl; aliphatic α-amino-β-hydroxy acids suchas serine, β-hydroxyleucine, β-hydroxynorleucine, β-hydroxynorvaline,and α-amino-β-hydroxystearic acid residues; α-Amino, α-, γ-, δ- orε-hydroxy acids such as homoserine, γ-hydroxynorvaline,δ-hydroxynorvaline and epsilon-hydroxynorleucine residues; canavinyl andcanalinyl; γ-hydroxyornithinyl; 2-Hexosaminic acids such asD-glucosaminic acid or D-galactosaminic acid residues; α-amino-β-thiolssuch as penicillamine, β-thiolnorvaline or β-thiolbutyrine residues;other sulfur containing amino acid residues including cysteine;homocystine; β-phenylmethionine; methionine; S-allyl-L-cysteinesulfoxide; 2-thiolhistidine; cystathionine; and thiol ethers of cysteineor homocysteine; phenylalanine, tryptophan and ring-substituted α aminoacids such as the phenyl- or cyclohexylamino acids α-aminophenylaceticacid, α-aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionicacid; phenylalanine analogues and derivatives comprising aryl, loweralkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur orhalo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-,p-chloro-, 3,4-dichloro, o-, m- or p-methyl-, 2,4,6-trimethyl-,2-ethoxy-5-nitro, 2-hydroxy-5-nitro and p-nitro-phenylalanine); furyl-,thienyl-, pyridyl-, pyrimidinyl-, purine or naphthylalanines; andtryptophan analogues and derivatives including kynurenine,3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophanresidues; α-amino substituted amino acid residues including sarcosine(N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine,N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline andN-benzylvaline; and α-Hydroxy and substituted α-hydroxy amino acidresidues including serine, threonine, allothreonine, phosphoserine andphosphothreonine residues.

Any one of the foregoing or other known amino acids are suitablyemployed in this invention. Typically amino acids are capable ofautocatalytically hydrolyzing the amino acid-steroid bond. Thus, theytypically contain, or upon being hydrolyzed in vivo, contain a freecarboxyl group or amine group.

Also of interest are hydrophobic amino acids such as mono- or di-alkylor aryl amino acids, cycloalkylamino acids and the like. These residues,together with R²⁹-R³⁴ (R³¹-R³⁴ are defined below) can contribute to cellpermeability by modulating the lipophilicity of a formula 1 or formula 2compound. Typically, the residue does not contain a sulfhydryl orguanidino substituent.

Peptide. One, 2, 3 or more of R¹-R⁴ can comprise a “peptide”, i.e., twoor more amino acids as defined above. Typically the amino acids arelinked through normal peptide bonds, i.e., —CO—NH—, between adjacentamino acid residues. Peptides comprise dipeptides (dimers), tripeptides(trimers), short peptides of 4, 5, 6, 8, 10 or 15 residues, and longerpeptides or proteins having about 100 or more residues. Inventioncompounds that comprise a peptide can be used as immunogens, prodrugs oras synthetic precursors for other steroid derivatives. In oneembodiment, the peptide will contain a peptidolytic enzyme cleavage siteat the peptide bond linking the first residue and the next residuedistal to the steroid residue. Such cleavage sites are optionallyflanked by enzymatic recognition structures, e.g. particular residuesrecognized by a hydrolytic enzyme, e.g., a peptidase located in theserum or in cells.

Peptidolytic enzymes are well known, and in particular includecarboxypeptidases. Carboxypeptidases digest polypeptides by removingC-terminal residues, and are specific in many instances for particularC-terminal sequences. Such enzymes and their substrate requirements ingeneral are well known. For example, a dipeptide having a given pair ofresidues and a free carboxyl terminus is covalently bonded through itsα-amino group to the steroid nucleus. It is expected that the peptidewill be cleaved by the appropriate dipeptidase, protease or by chemicalhydrolysis, leaving the carboxyl of the proximal amino acid residue toautocatalytically cleave the amidate bond.

Examples of suitable dipeptidyl groups (designated by their singleletter symbols) are shown in the table below.

SYMBOL 1-Letter 3-Letter AMINO ACID Y Tyr tyrosine G Gly glycine F Phephenylalanine M Met methionine A Ala alanine S Ser serine I Ileisoleucine L Leu leucine T Thr threonine V Val valine P Pro proline KLys lysine H His histidine Q Gln glutamine E Glu glutamic acid W Trptryptophan R Arg arginine D Asp aspartic acid N Asn asparagine C Cyscysteine

Dipeptides AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP,AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM,RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL,NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH,DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ,CG, CH, CI, CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC,EE, EQ, EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN,QD, QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA,GR, GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY,GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT,HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP,IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM,LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL,KK, KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH,MI, ML, MK, MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ,FG, FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC,PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN,SD, SC, SE, SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA,TR, TN, TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY,TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT,WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP,YS, YT, YW, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM,VF, VP, VS, VT, VW, VY, VV

Such dipeptides include species where both amino acids are in the Lconfiguration, the D configuration or mixtures of configurations.

Tripeptides, i.e., 3 linked amino acid residues, are also usefulembodiments. Tripeptides include those where A, C, D, E, F, G, H, I, K,L, M, N, P, Q, R, S, T, V, W or Y is linked by a standard peptide bondto the amino or the carboxyl terminus of any of the dipeptides listedabove. The sequence —X1-pro-X2-(where X1 is any amino acid and X2 ishydrogen, any amino acid residue or a carboxyl ester of proline) will becleaved by luminal carboxypeptidase to yield X1with a free carboxyl,which in turn autocatalytically cleaves the amidate bond. X2usually willbe a benzyl ester of the carboxy group of X2. Other embodiments includetetrapeptides such as ones where any two of the dipeptides listed above,which may be the same or different dipeptides (e.g., AA and AA linkedtogether or, e.g., AA and GI linked together), are linked to each otherby a peptide bond through the amino terminus or carboxyl terminus. One,2 or more tetrapeptides may be bonded to the formula 1 or formula 2compound through the tetrapeptide's amino or carboxyl terminus.

In some embodiments, the formula 1 or formula 2 compound comprises oneor more amino acids or peptides having the structure (A), (B) or (C):(A)R³²—NH-{[C(R²⁹)(R³⁰)]_(b)—C(O)—N(R³¹)}_(f)—[C(R²⁹)(R³⁰)]_(a)—C(O)—O-steroid,(B)R³³—O—{C(O)-[C(R²⁹)(R³⁰)]_(d)—N(R³¹)}_(g)—C(O)-[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—O-steroid,or (C)R³³—O-{C(O)-[C(R²⁹)(R³⁰)]_(d)—N(R³¹)}_(e)—C(O)-[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—C(O)—O-steroid,wherein (A), (B) or (C) are independently selected and they are bondedto 1, 2, 3 or more of R¹ through R⁴, where each R²⁹-R³¹ is independentlyselected; R²⁹ independently are —H or a C₁₋₂₀ organic moiety (e.g., C₁₋₆alkyl, e.g. —CH₃ or —C₂H₅); R³⁰ independently are the side chain of anamino acid, including the side chain of naturally occurring amino acidsas described above, e.g., —H, —CH₃, —CH₂C₆H₅; R³¹ is —H or a protectinggroup; R³² and R³³ independently comprise —H, a protecting group, anester or an amide where each atom or group is independently chosen; a,b, c and d independently are 1, 2, 3, 4 or 5, usually 1; e, f and gindependently are an integer from 0 to about 1000, typically theyindependently are 0, 1, 2, 3, 4, 5, 6, 7 or 8; a, b, c and dindependently are 1 or 2; e, f and g independently are 0, 1, 2, 3, 4 or5.

If the amino acid(s) or residue(s) has 2 or more amine groups, e.g., alysinyl or arginyl, or ornithinyl residue, then R²⁹ is usually —H andR³⁰ may comprise —[C(R³⁴)₂]_(n2)N(R^(PR))— where n2 is 0, 1, 2, 3, 4, 5or 6, R^(PR) is —H or a protecting group and each R³⁴ independently is—H, C₁-C₂₀ optionally substituted alkyl, C₆-C₂₀ optionally substitutedaryl, C₇-C₂₀ optionally substituted alkylaryl, C₇-C₂₀ optionallysubstituted arylalkyl, C₁-C₂₀ optionally substituted alkoxy, C₆-C₂₀optionally substituted aryloxy or hydroxyl. Such compounds will containa plurality of steroid moieties. For example when both the epsilon (ε)or delta (δ) and alpha (α) amino groups of lysine or ornithine aresubstituted with steroid moieties the amidate is believed to be capableof releasing two molecules of active drug, each expected to emerge underdifferent pharmacokinetics and therefore further sustaining the drugrelease.

Salt. Invention embodiments include salts and complexes of formula 1compounds, including pharmaceutically acceptable or salts that arerelatively non-toxic. Some of the compounds have one or more moietiesthat carry at least a partial positive or negative charge in aqueoussolutions, typically at a pH of about 4-10, that can participate informing a salt, a complex, a composition with partial salt and partialcomplex properties or other noncovalent interactions, all of which werefer to as a “salt(s)”. Salts are usually biologically compatible orpharmaceutically acceptable or non-toxic, particularly for mammaliancells. Salts that are biologically toxic are optionally used withsynthetic intermediates of invention compounds. When a water-solublecomposition is desired, monovalent salts are usually preferred.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which areoptionally prepared in this way are salts containing Li⁺, Na⁺, and K⁺. Aless soluble metal salt can be precipitated from the solution of a moresoluble salt by adding a suitable metal compound. Invention salts may beformed from acid addition of certain organic acids, such as organiccarboxylic acids, and inorganic acids, such as alkylsulfonic acids orhydrogen halide acids, to acidic or basic centers on inventioncompounds, such as basic centers on the invention pyrimidine baseanalogs. Metal salts include ones containing Na⁺, Li⁺, K⁺, Ca⁺⁺ or Mg⁺⁺.Other metal salts may contain aluminum, barium, strontium, cadmium,bismuth, arsenic or zinc ion.

Salt(s) of compounds may comprise a combination of appropriate cationssuch as alkali and alkaline earth metal ions or ammonium and quaternaryammonium ions with the acid anion moiety of the phosphoric acid orphosphonic acid group, which may be present in invention polymers ormonomers.

Salts are produced by standard methods, including dissolving free basein an aqueous, aqueous-alcohol or aqueous-organic solution containingthe selected acid, optionally followed by evaporating the solution. Thefree base is reacted in an organic solution containing the acid, inwhich case the salt usually separates directly or one can concentratethe solution.

Suitable amine salts include amines having sufficient basicity to form astable salt, preferably amines of low toxicity including trialkyl amines(tripropylamine, triethylamine, trimethylamine), procaine,dibenzylamine, N-benzyl-betaphenethylamine, ephenamine,N,N′-dibenzylethylenediamine, N-ethylpiperidine, benzylamine anddicyclohexylamine.

Salts include organic sulfonic acid or organic carboxylic acid salts,made for example by addition of the acids to basic centers, typicallyamines. Exemplary sulfonic acids include C₆₋₁₆ aryl sulfonic acids,C₆₋₁₆ heteroaryl sulfonic acids and C₁₋₁₆ alkyl sulfonic acids such asphenyl sulfonic acid, a-naphthalene sulfonic acid, β-naphthalenesulfonic acid, (S)-camphorsulfonic acid, methyl (CH₃SO₃H), ethyl(C₂H₅SO₃H), n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl,pentyl and hexyl sulfonic acids. Exemplary organic carboxylic acidsinclude C₁₋₁₆ alkyl, C₆₋₁₆ aryl carboxylic acids and C₄₋₁₆ heteroarylcarboxylic acids such as acetic, glycolic, lactic, pyruvic, malonic,glutaric, tartaric, citric, fumaric, succinic, malic, maleic, oxalic,hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,salicylic, nicotinic and 2-phenoxybenzoic.

Invention salts include those made from inorganic acids, e.g., HF, HCl,HBr, H₁, H₂SO₄, H₃PO₄, Na₂CO₃, K₂CO₃, CaCO₃, MgCO₃ and NaClO₃. Suitableanions, which are optionally present with a cation such a Ca⁺⁺, Mg⁺⁺,Li⁺, Na⁺ or K⁺, include formate, sorbate, glycodeoxycholate, cholate,deoxycholate, desoxycholate, taurocholate, taurodeoxycholate,taurolithocholate, tetraborate, nitrate, nitrite, sulfite, sulfamate,hyposulfite, bisulfite, metabisulfite, thiosulfate, silicate,metasilicate, gluconate, gulcuronate, hippurate, hydrosulfite, borate,metaborate and urate.

Salts also include the invention compound salts with one or more aminoacids. Many amino acids are suitable, especially the naturally-occurringamino acids found as protein components, although the amino acidtypically is one bearing a side chain with a basic or acidic group,e.g., lysine, arginine, histidine or glutamic acid, or a neutral groupsuch as glycine, serine, threonine, alanine, isoleucine, or leucine.

The invention compositions include compounds in their un-ionized, aswell as zwitterionic form, and combinations with stoiochiometric amountsof water as in hydrates.

Stereoisomers. The formula 1 compounds include enriched or resolvedoptical isomers at any or all asymmetric atoms as are apparent from thedepictions. Both racemic and diasteromeric mixtures, as well as theindividual optical isomers can be isolated or synthesized so as to besubstantially free of their enantiomeric or diastereomeric partners, andthese are all within the scope of the invention. Chiral centers may befound in invention compounds at, for example, R¹, R², R³, R⁴, R⁵ or R⁶.

One or more of the following methods are used to prepare theenantiomerically enriched or pure isomers herein. The methods are listedin approximately their order of preference, i.e., one ordinarily shouldemploy stereospecific synthesis from chiral precursors beforechromatographic resolution or before spontaneous crystallization.

Stereospecific synthesis is conveniently used when the appropriatechiral starting material is available and reaction steps are chosen thatdo not result in undesired racemization at chiral sites. One advantageof stereospecific synthesis is that it does not produce undesiredenantiomers that must be removed from the final product, therebylowering overall synthetic yield. In general, those skilled in the artwould understand what starting materials and reaction conditions shouldbe used to obtain the desired enantiomerically enriched or pure isomersby stereospecific synthesis.

Another synthesis method of general utility is chromatographicresolution of enantiomers on chiral chromatography resins. These resinsare packed in columns, commonly called Pirkle columns, and arecommercially available. The columns contain a chiral stationary phase.The racemate is placed in solution and loaded onto the column, andthereafter separated by HPLC. See for example, ProceedingsChromatographic Society—International Symposium on Chiral Separations,Sep. 3-4, 1987. Examples of chiral columns that could be used to screenfor the optimal separation technique would include Diacel Chriacel OD,Regis Pirkle Covalent D-phenylglycine, Regis Pirkle Type 1A, AstecCyclobond II, Astec Cyclobond III, Serva Chiral D-DL=Daltosil 100,Bakerbond DNBLeu, Sumipax OA-1000, Merck Cellulose Triacetate column,Astec Cyclobond I-Beta, or Regis Pirkle Covalent D-Naphthylalanine. Notall of these columns are likely to be effective with every racemicmixture. However, those skilled in the art understand that a certainamount of routine screening may be required to identify the mosteffective stationary phase. When using such columns it is desirable toemploy embodiments of the compounds of this invention in which thecharges are not neutralized, e.g., where acidic functionalities such ascarboxyl are not esterified or amidated.

Another method entails converting the enantiomers in the mixture todiasteriomers with chiral auxiliaries and then separating the conjugatesby ordinary column chromatography. This is a very suitable method,particularly when the embodiment contains free carboxyl, amino orhydroxyl that will form a salt or covalent bond to a chiral auxiliary.Chirally pure amino acids, organic acids or organosulfonic acids are allworthwhile exploring as chiral auxiliaries, all of which are well knownin the art. Salts with such auxiliaries can be formed, or they can becovalently (but reversibly) bonded to the functional group. For example,pure D or L amino acids can be used to amidate the carboxyl group ofinvention embodiments that comprise a carboxyl group and then separatedby chromatography.

Enzymatic resolution is another method of potential value. In suchmethods one prepares covalent derivatives of the enantiomers in theracemic mixture, generally lower alkyl esters (for example of carboxyl),and then exposes the derivative to enzymatic cleavage, generallyhydrolysis. For this method to be successful an enzyme must be chosenthat is capable of stereospecific cleavage, so it is frequentlynecessary to routinely screen several enzymes. If esters are to becleaved, then one selects a group of esterases, phosphatases, andlipases and determines their activity on the derivative. Typicalesterases are from liver, pancreas or other animal organs, and includeporcine liver esterase.

If the enantiomeric mixture separates from solution or a melt as aconglomerate, i.e., a mixture of enantiomerically-pure crystals, thenthe crystals can be mechanically separated, thereby producing theenantiomerically enriched preparation. This method, however, is notpractical for large scale preparations and is of limited value for trueracemic compounds.

Asymmetric synthesis is another technique for achieving enantiomericenrichment. For example, a chiral protecting group is reacted with thegroup to be protected and the reaction mixture allowed to equilibrate.If the reaction is enantiomerically specific then the product will beenriched in that enantiomer.

Further guidance in the separation of enantiomeric mixtures can befound, by way of example and not limitation, in “Enantiomers, Racemates,and resolutions”, Jean Jacques, Andre Collet, and Samuel H. Wilen(Krieger Publishing Company, Malabar, Fla., 1991, ISBN 0-89464-618-4):Part 2, Resolution of Enantiomer Mixture, pages 217-435; moreparticularly, section 4, Resolution by Direct Crystallization, pages217-251, section 5, Formation and Separation of Diastereomers, pages251-369, section 6, Crystallization-induced Asymmetric Transformations,pages 369-378, and section 7, Experimental Aspects and Art ofResolutions, pages 378-435; still more particularly, section 5.1.4,Resolution of Alcohols, Transformation of Alcohols into Salt-FormingDerivatives, pages 263-266, section 5.2.3, Covalent Derivatives ofAlcohols, Thiols, and Phenols, pages 332-335, section 5.1.1, Resolutionof Acids, pages 257-259, section 5.1.2, Resolution of Bases, pages259-260, section 5.1.3, Resolution of Amino Acids, page 261-263, section5.2.1, Covalent Derivatives of Acids, page 329, section 5.2.2, Covalentderivatives of Amines, pages 330-331, section 5.2.4, CovalentDerivatives of Aldehydes, Ketones, and Sulfoxides, pages 335-339, andsection 5.2.7, Chromatographic Behavior of Covalent Diastereomers, pages348-354.

The formula 1 and 2 compounds, e.g., EED,17α-ethynyl-androst-5-ene-3β,17-diol,3β,17b-dihydroxy-androst-5-ene-16-one or an amino acid, peptide,carbonate, ester, thioester, monosaccharide or disaccharide derivativeor prodrug of any of these compounds or3β-methylcarbonate-androst-5-ene-7,17 dione, are useful to treatconditions that are associated with or that respond to modulation of ARactivity, including prostate cancer, acne, male pattern baldness,hirsutism, hypogonadism and breast cancer. These compounds may beoptionally be used in combination therapies to treat any of thesediseases or conditions. The combinations include a formula 1 or 2compound(s) combined with surgery, radiation therapy, cytotoxic agents,cytostatic agents or hormone therapies, including any of the therapiesor treatments disclosed herein or in any of the references cited herein.

The formula 1 or 2 compounds are also useful to determine if the AR oranother steroid receptor, e.g., an orphan receptor, are present in acell population or cell extract. In these applications, the compoundswill typically be labeled, e.g., radiolabels (¹⁴C, ³H, ³²P, ³⁵S or aradioactive iodine isotope) or labeled with a crosslinking moiety. Inrelated applications, the compounds are useful as reference standards tocompare their capacity to modulate AR activity with the capacity ofknown AR modulators, such as AED. In these applications, a formula 1 or2 compound is used in a suitable assay system, e.g., one that comprisescells (in vitro or in vivo) that contain functional AR, an AR-responsivegene, e.g., ornithine carboxylase, that can be conveniently assayed, aformula 1 or 2 compound and a test compound. In such methods, the effectof the formula 1 or 2 compound on the capacity of the test compound tomodulate the AR is examined, usually using a suitably controlled system,e.g., with varying concentrations of the formula 1 or 2 compound, orvarying concentrations of the test compound. Assay systems, orcomponents thereof that comprise the Ar have been described, see, e.g.,U.S. Pat. Nos. 4,981,784 and 5,071,773, Evans, et al., Science240:889-895 1988, T. Berger et al., J. Steriod Biochem. Molec. Biol.41:773-778 1992, J. Simenthal, et al., J. Biol. Chem. 266:510-514 1991,G. Scalabrino et al., Mol. Cell. Endocrinol. 77:1-35 1991, O. Janne, etal., Ann. N.Y. Acad. Sci. 438:72-84 1984, and R. Djurhuus, Anal.Biochem. 113:352-355 1981.

An effective dose of a formula 1 or formula 2 compound, or the “activeingredient”, for use in therapeutic applications, e.g., prostate cancertreatment, will depend to a certain extent at least on factors such asthe status of the condition being treated, whether the compound(s) isbeing used prophylactically (lower doses) or the severity of themalignancy, the method of delivery, and the pharmaceutical formulation.These factors will be determined by the clinician using conventionaldose escalation studies. Typically the dose administered to the subjectwill be from about 0.03 to about 30 mg/kg body weight per day, generallyabout 0.1 to about 10 mg/kg body weight per day. For example, fortopical delivery the daily candidate dose for an adult human ofapproximately 70 kg body weight will range from about 1 mg to about 750mg, generally between about 5 mg and about 300 mg, usually between about30 mg and about 250 mg. A daily dose may take the form of single ormultiple doses or administration sites. For a formula 1 or 2 compoundthat is delivered parenterally, e.g., i.v., s.c. or i.m., the dose willgenerally be lower (e.g., about 0.02 to about 6 mg/kg) than a doseadministered orally.

Pharmaceutical formulations that comprise a formula 1 or 2 compound willtypically comprise one or more carriers or excipients and optionallyother therapeutic ingredients. The carrier(s) will generally be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and physiologically innocuous to the recipientthereof. Such carriers or excipients are known, e.g., fillers,lubricants, binders and various liquid excipients for liquidformulations. Suitable carriers include those disclosed in thereferences cited herein.

Suitable formulations include aqueous or oily solutions of the activeingredient. Formulations suitable for parenteral delivery of the activeingredient include aqueous and non-aqueous compositions where the activeingredient is dissolved or suspended in solution. Such formulations willtypically comprise about 25-300 mg/mL of the active ingredient, usuallyabout 40-200 mg/mL. Formulations suitable for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats or solutes that render theformulation isotonic with the blood of the intended recipient. Otherparenteral formulations may comprise aqueous and non-aqueous sterilesuspensions which may include suspending agents and thickening agents.

Formulations suitable for topical administration include creams orointments wherein the formula 1 or 2 compound is dissolved or suspendedin a suitable carrier, especially a non-aqueous solvent or carrier forthe active ingredient. The active ingredient is typically present insuch formulations in a concentration of 0.5 to 20% w/w, often 0.5 to 10%w/w. Such formulations are suitable for use in applications such astreating male pattern baldness or acne.

Formulations suitable for buccal or sublingual administration includelozenges comprising the active ingredient, which is optionally presentin a flavored basis such as sucrose and acacia or tragacanth. Pastillesmay comprise the active ingredient in an inert basis such as gelatin andglycerin, or sucrose and acacia, and mouthwashes may comprise the activeingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration willhave a particle size for example in the range of 0.01 to 200 microns(including particle sizes in a range between 0.01 and 500 microns inincrements of 0.1 microns such as 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 5, 30microns, 35 microns, etc.), which is administered by inhalation throughthe nasal passage or by inhalation through the mouth so as to reach thevarious bronchi or alveolar sacs. Formulations suitable for aerosol ordry powder administration may be prepared according to conventionalmethods and may be delivered with other therapeutic agents such ascompounds heretofore used in the treatment or prophylaxis of prostatecancer.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations comprising an active ingredient are presented in unit-doseor multi-dose containers, for example sealed ampoules and vials, and maybe stored in a freeze-dried (lyophilized) condition requiring only theaddition of the sterile liquid carrier, for example water for injection,immediately prior to use. Extemporaneous injection solutions andsuspensions are prepared from sterile powders, granules and tablets ofthe kind previously described. Preferred unit dosage formulations arethose containing a daily dose or unit daily sub-dose, as describedherein, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring or coloring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient together with a veterinary carrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

The active ingredients may be used to provide controlled releasepharmaceutical formulations containing an active ingredient (“controlledrelease formulations”) in which the release of the active ingredient iscontrolled and regulated to allow less frequency dosing or to improvethe pharmacokinetic or toxicity profile of a given active ingredient.

The formulations include those suitable for any of the foregoingadministration routes. The formulations may conveniently be presented inunit dosage form and may be prepared by any of the methods well known inthe art of pharmacy. Techniques and formulations generally are found inRemington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).Such methods include the step of bringing into association the activeingredient with the carrier which constitutes one or more accessoryingredients or excipients. In general, the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both, and then,if necessary, shaping the product.

Formulations of the invention suitable for oral administration areprepared as discrete units such as capsules, cachets or tablets eachcontaining a predetermined amount of the active ingredient; as a powderor granules; as solution or a suspension in an aqueous liquid or anon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

If desired, the aqueous phase of a cream base may include, for example,polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groupssuch as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glyceroland polyethylene glycol and mixtures thereof. The topical formulationsmay desirably include a compound which enhances absorption orpenetration of the active ingredient through the skin or other affectedareas. Examples of such dermal penetration enhancers include dimethylsulphoxide and related analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween™ 60, Span™ 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

In some embodiments, the methods or compositions described herein willutilize, in lieu of a formula 1 or 2 compound, one or more steroid ornon-steroid compounds that are disclosed in U.S. Pat. Nos. 2,833,793,2,911,418, 3,148,198, 3,471,480, 3,710,795, 3,711,606 3,976,691,4,268,441, 4,427,649, 4,542,129, 4,666,898, 4,693,999, 4,978,532,5,001,119, 5,043,165, 5,077,284, 5,028,631, 5,110,810, 5,157,031,5,162,198, 5,175,154, 5,277,907, 5,292,730, 5,296,481, 5,372,996,5,387,583, 5,407,684, 5,424,463, 5,461,042, 5,478,566, 5,506,223,5,518,725, 5,527,788, 5,527,789, 5,532,230, 5,559,107, 5,562,910,5,583,126, 5,585,371, 5,587,369, 5,591,736, 5,593,981, 5,610,150,5,635,496, 5,641,766, 5,641,768, 5,656,621, 5,660,835, 5,677,336,5,681,835 5,686,438, 5,696,106, 5,696,127, 5,696,130, 5,700,793,5,707,983, 5,709,878, 5,710,143, 5,714,481, 5,728,688, 5,736,537,5,744,462, 5,753,237, 5,756,482, 5,776,921, 5,776,923, 5,780,460,5,780,676, 5,795,880, 5,798,347, 5,798,348, 5,804,576, 5,807,848,5,807,849, 5,811,418, 5,824,313, 5,824,668, 5,824,671, 5,827,841,5,837,269, 5,837,700, 5,843,932, 5,846,963, 5,856,340, 5,859,000,5,869,090, 5,863,910, 5,872,114, 5,872,147, 5,886,005, 5,889,042,5,891,865, 5,892,069, 5,945,404 or 5,945,412 or in PCT publicationnumber 97/49709.

The positions in the rings of formula 1 compounds are numbered as shownbelow.

More than one double bond may be present in formula 1 compounds, but nocarbon atom will carry a charge due to the presence of excess bonds orvalences. Typically, 0, 1, 2, 3 or 4 double bonds will be present. Thus,if a double bond is present at the 5-6-positions, R⁹ and one of R¹⁰ andR¹¹ will be absent. Or, if one or both of the variable groups that arebonded to the ring atoms comprises a double bond, e.g., ═CH₂, ═CHCH₃,═N—NH₂, ═O or ═S, there will be no double bond in the ring at those ringatom positions. The A ring may comprise 0, 1, 2 or 3 double bonds andthat ring may thus be aromatic. The B and D rings may independentlycomprise 0, 1 or 2 double bonds and the C ring may comprise 1 doublebond. When one or both of R²⁴ and R²⁵ are present, they independentlyare in the α- or β-configurations, and in some embodiments, they areindependently —CH₃ or —CH₂OH in the β-configuration.

Compounds of formula 2 have the structure

wherein R²⁶-R²⁸ independently comprise —H, —OR^(PR), —SR^(PR),—N(R^(PR))₂, —O—Si—(R^(A))₃, —CN, —NO₂, an ester, a phosphoester, aphosphonoester, a sulfite ester, a sulfate ester, an amide, an aminoacid, a peptide, an ether, a thioether, an acyl group, a carbonate, acarbamate, a carboxyl, a halogen, an optionally substituted alkyl group,an optionally substituted alkenyl group, an optionally substitutedalkynyl group, an optionally substituted aryl moiety, an optionallysubstituted heteroaryl moiety, an optionally substituted monosaccharide,an optionally substituted oligosaccharide, a nucleoside, a nucleotide,an oligonucleotide, a polymer, or, R²⁶ and R²⁷ or R²⁴ and R²⁸ takentogether independently comprise ═O or ═S.

In some embodiments, one, two, three, four or more of R¹-R²⁸independently comprise —OH, ═O, —SH, ═S, —NH₂, halogen, ═CH₂, ═NOH,═NOC(O)CH₃, —O—C(O)—(CH₂)_(m)—(CF₂)_(n)—CH₃,—O—C(O)—(CH₂)_(m)—(CF₂)_(n)—CF₃, —O—C(O)—(CH₂)_(m)—(CF₂)_(n)—CH₂F,—O—C(O)—O—(CH₂)_(m)—(CF₂)_(n)—CH₃, —O—C(O)—O—(CH₂)_(m)—(CF₂)_(n)—CF₃,—O—C(O)—O—(CH₂)_(m)—(CF₂)_(n)—CH₂F, —O—C(O)—NH—(CH₂)_(m)—(CF₂)_(n)—CH₃,—O—C(O)—NH—(CH₂)_(m)—(CF₂)_(n)—CF₃, —O—C(O)—NH—(CH₂)_(m)—(CF₂)_(n)—CH₂F(where m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9 or 10, usually n is 0), —CH(CH₃)—(CH₂)₂—C(O)NH—CH₂COOH,—CH(CH₃)—(CH₂)₂—C(O)NH—CH₂SO₃H, —OSi(CH₃)₂C(CH₃)₃, —C(OH)═CHCH₃,═CH(CH₂)₀₋₁₅CH₃, —(CH₂)₀₋₁₄—CH₂F, —(CH₂)₀₋₁₄—CH₂Cl, —(CH₂)₀₋₁₄—CH₂Br,—(CH₂)₀₋₁₄—CH₂I, —(CH₂)₂₋₁₀—O—(CH₂)₀₋₄—CH₃, —(CH₂)₂₋₁₀—S—(CH₂)₀₋₄—CH₃,—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄—CH₃, —O—(CH₂)₀₋₁₄—CH₂F, —O—(CH₂)₀₋₁₄—CH₂Cl,—O—(CH₂)₀₋₁₄—CH₂Br, —O—(CH₂)₀₋₁₄—CH₂I, —O—(CH₂)₂₋₁₀—O—(CH₂)₀₋₄—CH₃,—O—(CH₂)₂₋₁₀—S—(CH₂)₀₋₄—CH₃, —O—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄—CH₃,—O—C(O)—(CH₂)₀₋₁₄—CH₂F, —O—C(O)—(CH₂)₀₋₁₄—CH₂Cl,—O—C(O)—(CH₂)₀₋₁₄—CH₂Br, —O—C(O)—(CH₂)₀₋₁₄—CH₂I,—O—C(O)—(CH₂)₂₋₁₀—O—(CH₂)₀₋₄—CH₃, —O—C(O)—(CH₂)₂₋₁₀—S—(CH₂)₀₋₄—CH₃,—O—C(O)—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄—CH₃, —O—C(S)—(CH₂)₀₋₁₄—CH₂F,—O—C(S)—(CH₂)₀₋₁₄—CH₂Cl, —O—C(S)—(CH₂)₀₋₁₄—CH₂Br,—O—C(S)—(CH₂)₀₋₁₄—CH₂I, —O—C(S)—(CH₂)₂₋₁₀—(CH₂)₀₋₄—CH₃,—O—C(S)—(CH₂)₂₋₁₀—S—(CH₂)₀₋₄—CH₃, —O—C(S)—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄—CH₃,—(CH₂)₀₋₁₆NH₂, —(CH₂)₀₋₁₅CH₃, —(CH₂)₀₋₁₅CN, —(CH₂)₀₋₁₅CH═CH₂,—(CH₂)₀₋₁₅NHCH(O), —(CH₂)₀₋₁₆NH—(CH₂)₀₋₁₅CH₃, —(CH₂)₀₋₁₅CCH,—(CH₂)₀₋₁₅OC(O)CH₃, —(CH₂)₀₋₁₅OCH(OH)CH₃, —(CH₂)₀₋₁₅C(O)OCH₃,—(CH₂)₀₋₁₅C(O)OCH₂CH₃, —(CH₂)₀₋₁₅C(O)(CH₂)₀₋₁₅CH₃,—(CH₂)₀₋₁₅C(O)(CH₂)₀₋₁₅CH₂OH, —O(CH₂)₁₋₁₆NH₂, —O(CH₂)₁₋₁₅CH₃,—O(CH₂)₁₋₁₅CN, —O(CH₂)₁₋₁₅CH═CH₂, —O(CH₂)₁₋₁₅NHCH(O),—O(CH₂)₁₋₁₆NH—(CH₂)₁₋₁₅CH₃, —O(CH₂)₁₋₁₅CCH, —O(CH₂)₁₋₁₅OC(O)CH₃,—O(CH₂)₁₋₁₅OCH(OH)CH₃, —O(CH₂)₁₋₁₅C(O)OCH₃, —O(CH₂)₁₋₁₅C(O)OCH₂CH₃,—O(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₃, —O(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₂OH,—OC(O)(CH₂)₁₋₁₆NH₂, —OC(O)(CH₂)₁₋₁₅CH₃, —C(O)O(CH₂)₁₋₁₅CN,—C(O)O(CH₂)₁₋₁₅CH═CH₂, —OC(O)(CH₂)₁₋₁₅NHCH(O),—OC(O)(CH₂)₁₋₁₆NH—(CH₂)₁₋₁₅CH₃, —OC(O)(CH₂)₁₋₁₅CCH,—OC(O)(CH₂)₁₋₁₅OC(O)CH₃, —OC(O)(CH₂)₁₋₁₅OCH(OH)CH₃,—OC(O)(CH₂)₁₋₁₅C(O)OCH₃, —OC(O)(CH₂)₁₋₁₅C(O)OCH₂CH₃,—OC(O)(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₃, —OC(O)(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₂OH,—C(O)—O—(CH₂)_(m)CH₃ (where m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10),—(CH₂)_(m)—C(O)OH (where m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10),phosphoenolpyruvate, D-glucosamine, glucholic acid, glucuronic acid,pantothenic acid, pyruvic acid, glucose, fructose, mannose, sucrose,lactose, glycerol, 3-phosphoglycerate, a PEG (PEG 20, PEG 100, PEG 200,PEG 10000), a polyoxyalkylene polymer, glycine, alanine, phenylalanine,glutamic acid, lysine, threonine, proline and/or 4-hydroxyproline. Suchsubstituents may be present in the α-configuration or theβ-configuration.

Enumerated embodiments. By way of examples that further illustrate theformula 1 compounds, compounds or genera of compounds are named asdescribed in the following groups of compounds.

Group 1 compounds. Compounds or genera of compounds are named in Table2. Each named group 1 compound or genus is a compound or genus offormula 3

wherein R⁷, R⁸, R¹⁴ and R¹⁵ are all —H, and R²⁴ and R²⁵ are both —CH₃.The Table 2 compounds are named by numbers that specify the structuresof the R⁵, R⁶, R¹², R¹³, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ variable groups in Table1 as follows R⁵R⁶.R¹²R¹³.R¹⁶R¹⁷.R¹⁸R¹⁹. In some embodiments, 2 variablegroups that are linked to the same carbon atom are taken together toform a double bonded moiety, e.g., ═O, ═CH₂. Thus, based on thestructures shown in Table 1, the compounds named 4.2.2.3, 4.3.2.3 and8.1.6.10 in Table 2 have the structures

TABLE 1 R⁵, R⁶ R¹², R¹³ 1 —OH, —H 1 —H, —H 2 —H, —OH 2 —OH, —H 3 —OH,—OH 3 —H, —OH 4 —O—C(O)—OCH₃, —H 4 —OH, —OH 5 —H, —O—C(O)—OCH₃ 5—O—C(O)—OCH₃, —H 6 —O—CH₂—C₆H₅, —H 6 —H, —O—C(O)—OCH₃ 7 —H, —O—CH₂—C₆H₅7 ═O 8 —O—C(O)—CH₃, —H 8 ═S 9 —H, —O—C(O)—CH₃ 9 —SH, —H 10 ═O 10 —H, —SHR¹⁶, R¹⁷ R¹⁸, R¹⁹ 1 —H, —H 1 —OH, —H 2 ═O 2 —H, —OH 3 ═CH₂ 3 —OH, —CCH 4═S 4 —CCH, —OH 5 —OH, —H 5 —H, —CCH 6 —H, —OH 6 —CCH, —H 7 —O—C(O)—OCH₃,—H 7 —OH, —CCCH₃ 8 —H, —O—C(O)—OCH₃ 8 —O—C(O)—CH₃, —CCH 9 —O—C(O)—CH₃,—H 9 —O—C(O)—CH₂CH₃, —CCH 10 —H, —O—C(O)—CH₃ 10 ═O

TABLE 2 1.1.1.1, 1.1.1.2, 1.1.1.3, 1.1.1.4, 1.1.1.5, 1.1.1.6, 1.1.1.7,1.1.1.8, 1.1.1.9, 1.1.1.10, 1.1.2.1, 1.1.2.2, 1.1.2.3, 1.1.2.4, 1.1.2.5,1.1.2.6, 1.1.2.7, 1.1.2.8, 1.1.2.9, 1.1.2.10, 1.1.3.1, 1.1.3.2, 1.1.3.3,1.1.3.4, 1.1.3.5, 1.1.3.6, 1.1.3.7, 1.1.3.8, 1.1.3.9, 1.1.3.10, 1.1.4.1,1.1.4.2, 1.1.4.3, 1.1.4.4, 1.1.4.5, 1.1.4.6, 1.1.4.7, 1.1.4.8, 1.1.4.9,1.1.4.10, 1.1.5.1, 1.1.5.2, 1.1.5.3, 1.1.5.4, 1.1.5.5, 1.1.5.6, 1.1.5.7,1.1.5.8, 1.1.5.9, 1.1.5.10, 1.1.6.1, 1.1.6.2, 1.1.6.3, 1.1.6.4, 1.1.6.5,1.1.6.6, 1.1.6.7, 1.1.6.8, 1.1.6.9, 1.1.6.10, 1.1.7.1, 1.1.7.2, 1.1.7.3,1.1.7.4, 1.1.7.5, 1.1.7.6, 1.1.7.7, 1.1.7.8, 1.1.7.9, 1.1.7.10, 1.1.8.1,1.1.8.2, 1.1.8.3, 1.1.8.4, 1.1.8.5, 1.1.8.6, 1.1.8.7, 1.1.8.8, 1.1.8.9,1.1.8.10, 1.1.9.1, 1.1.9.2, 1.1.9.3, 1.1.9.4, 1.1.9.5, 1.1.9.6, 1.1.9.7,1.1.9.8, 1.1.9.9, 1.1.9.10, 1.1.10.1, 1.1.10.2, 1.1.10.3, 1.1.10.4,1.1.10.5, 1.1.10.6, 1.1.10.7, 1.1.10.8, 1.1.10.9, 1.1.10.10, 1.2.1.1,1.2.1.2, 1.2.1.3, 1.2.1.4, 1.2.1.5, 1.2.1.6, 1.2.1.7, 1.2.1.8, 1.2.1.9,1.2.1.10, 1.2.2.1, 1.2.2.2, 1.2.2.3, 1.2.2.4, 1.2.2.5, 1.2.2.6, 1.2.2.7,1.2.2.8, 1.2.2.9, 1.2.2.10, 1.2.3.1, 1.2.3.2, 1.2.3.3, 1.2.3.4, 1.2.3.5,1.2.3.6, 1.2.3.7, 1.2.3.8, 1.2.3.9, 1.2.3.10, 1.2.4.1, 1.2.4.2, 1.2.4.3,1.2.4.4, 1.2.4.5, 1.2.4.6, 1.2.4.7, 1.2.4.8, 1.2.4.9, 1.2.4.10, 1.2.5.1,1.2.5.2, 1.2.5.3, 1.2.5.4, 1.2.5.5, 1.2.5.6, 1.2.5.7, 1.2.5.8, 1.2.5.9,1.2.5.10, 1.2.6.1, 1.2.6.2, 1.2.6.3, 1.2.6.4, 1.2.6.5, 1.2.6.6, 1.2.6.7,1.2.6.8, 1.2.6.9, 1.2.6.10, 1.2.7.1, 1.2.7.2, 1.2.7.3, 1.2.7.4, 1.2.7.5,1.2.7.6, 1.2.7.7, 1.2.7.8, 1.2.7.9, 1.2.7.10, 1.2.8.1, 1.2.8.2, 1.2.8.3,1.2.8.4, 1.2.8.5, 1.2.8.6, 1.2.8.7, 1.2.8.8, 1.2.8.9, 1.2.8.10, 1.2.9.1,1.2.9.2, 1.2.9.3, 1.2.9.4, 1.2.9.5, 1.2.9.6, 1.2.9.7, 1.2.9.8, 1.2.9.9,1.2.9.10, 1.2.10.1, 1.2.10.2, 1.2.10.3, 1.2.10.4, 1.2.10.5, 1.2.10.6,1.2.10.7, 1.2.10.8, 1.2.10.9, 1.2.10.10, 1.3.1.1, 1.3.1.2, 1.3.1.3,1.3.1.4, 1.3.1.5, 1.3.1.6, 1.3.1.7, 1.3.1.8, 1.3.1.9, 1.3.1.10, 1.3.2.1,1.3.2.2, 1.3.2.3, 1.3.2.4, 1.3.2.5, 1.3.2.6, 1.3.2.7, 1.3.2.8, 1.3.2.9,1.3.2.10, 1.3.3.1, 1.3.3.2, 1.3.3.3, 1.3.3.4, 1.3.3.5, 1.3.3.6, 1.3.3.7,1.3.3.8, 1.3.3.9, 1.3.3.10, 1.3.4.1, 1.3.4.2, 1.3.4.3, 1.3.4.4, 1.3.4.5,1.3.4.6, 1.3.4.7, 1.3.4.8, 1.3.4.9, 1.3.4.10, 1.3.5.1, 1.3.5.2, 1.3.5.3,1.3.5.4, 1.3.5.5, 1.3.5.6, 1.3.5.7, 1.3.5.8, 1.3.5.9, 1.3.5.10, 1.3.6.1,1.3.6.2, 1.3.6.3, 1.3.6.4, 1.3.6.5, 1.3.6.6, 1.3.6.7, 1.3.6.8, 1.3.6.9,1.3.6.10, 1.3.7.1, 1.3.7.2, 1.3.7.3, 1.3.7.4, 1.3.7.5, 1.3.7.6, 1.3.7.7,1.3.7.8, 1.3.7.9, 1.3.7.10, 1.3.8.1, 1.3.8.2, 1.3.8.3, 1.3.8.4, 1.3.8.5,1.3.8.6, 1.3.8.7, 1.3.8.8, 1.3.8.9, 1.3.8.10, 1.3.9.1, 1.3.9.2, 1.3.9.3,1.3.9.4, 1.3.9.5, 1.3.9.6, 1.3.9.7, 1.3.9.8, 1.3.9.9, 1.3.9.10,1.3.10.1, 1.3.10.2, 1.3.10.3, 1.3.10.4, 1.3.10.5, 1.3.10.6, 1.3.10.7,1.3.10.8, 1.3.10.9, 1.3.10.10, 1.4.1.1, 1.4.1.2, 1.4.1.3, 1.4.1.4,1.4.1.5, 1.4.1.6, 1.4.1.7, 1.4.1.8, 1.4.1.9, 1.4.1.10, 1.4.2.1, 1.4.2.2,1.4.2.3, 1.4.2.4, 1.4.2.5, 1.4.2.6, 1.4.2.7, 1.4.2.8, 1.4.2.9, 1.4.2.10,1.4.3.1, 1.4.3.2, 1.4.3.3, 1.4.3.4, 1.4.3.5, 1.4.3.6, 1.4.3.7, 1.4.3.8,1.4.3.9, 1.4.3.10, 1.4.4.1, 1.4.4.2, 1.4.4.3, 1.4.4.4, 1.4.4.5, 1.4.4.6,1.4.4.7, 1.4.4.8, 1.4.4.9, 1.4.4.10, 1.4.5.1, 1.4.5.2, 1.4.5.3, 1.4.5.4,1.4.5.5, 1.4.5.6, 1.4.5.7, 1.4.5.8, 1.4.5.9, 1.4.5.10, 1.4.6.1, 1.4.6.2,1.4.6.3, 1.4.6.4, 1.4.6.5, 1.4.6.6, 1.4.6.7, 1.4.6.8, 1.4.6.9, 1.4.6.10,1.4.7.1, 1.4.7.2, 1.4.7.3, 1.4.7.4, 1.4.7.5, 1.4.7.6, 1.4.7.7, 1.4.7.8,1.4.7.9, 1.4.7.10, 1.4.8.1, 1.4.8.2, 1.4.8.3, 1.4.8.4, 1.4.8.5, 1.4.8.6,1.4.8.7, 1.4.8.8, 1.4.8.9, 1.4.8.10, 1.4.9.1, 1.4.9.2, 1.4.9.3, 1.4.9.4,1.4.9.5, 1.4.9.6, 1.4.9.7, 1.4.9.8, 1.4.9.9, 1.4.9.10, 1.4.10.1,1.4.10.2, 1.4.10.3, 1.4.10.4, 1.4.10.5, 1.4.10.6, 1.4.10.7, 1.4.10.8,1.4.10.9, 1.4.10.10, 1.5.1.1, 1.5.1.2, 1.5.1.3, 1.5.1.4, 1.5.1.5,1.5.1.6, 1.5.1.7, 1.5.1.8, 1.5.1.9, 1.5.1.10, 1.5.2.1, 1.5.2.2, 1.5.2.3,1.5.2.4, 1.5.2.5, 1.5.2.6, 1.5.2.7, 1.5.2.8, 1.5.2.9, 1.5.2.10, 1.5.3.1,1.5.3.2, 1.5.3.3, 1.5.3.4, 1.5.3.5, 1.5.3.6, 1.5.3.7, 1.5.3.8, 1.5.3.9,1.5.3.10, 1.5.4.1, 1.5.4.2, 1.5.4.3, 1.5.4.4, 1.5.4.5, 1.5.4.6, 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10.5.1.4, 10.5.1.5,10.5.1.6, 10.5.1.7, 10.5.1.8, 10.5.1.9, 10.5.1.10, 10.5.2.1, 10.5.2.2,10.5.2.3, 10.5.2.4, 10.5.2.5, 10.5.2.6, 10.5.2.7, 10.5.2.8, 10.5.2.9,10.5.2.10, 10.5.3.1, 10.5.3.2, 10.5.3.3, 10.5.3.4, 10.5.3.5, 10.5.3.6,10.5.3.7, 10.5.3.8, 10.5.3.9, 10.5.3.10, 10.5.4.1, 10.5.4.2, 10.5.4.3,10.5.4.4, 10.5.4.5, 10.5.4.6, 10.5.4.7, 10.5.4.8, 10.5.4.9, 10.5.4.10,10.5.5.1, 10.5.5.2, 10.5.5.3, 10.5.5.4, 10.5.5.5, 10.5.5.6, 10.5.5.7,10.5.5.8, 10.5.5.9, 10.5.5.10, 10.5.6.1, 10.5.6.2, 10.5.6.3, 10.5.6.4,10.5.6.5, 10.5.6.6, 10.5.6.7, 10.5.6.8, 10.5.6.9, 10.5.6.10, 10.5.7.1,10.5.7.2, 10.5.7.3, 10.5.7.4, 10.5.7.5, 10.5.7.6, 10.5.7.7, 10.5.7.8,10.5.7.9, 10.5.7.10, 10.5.8.1, 10.5.8.2, 10.5.8.3, 10.5.8.4, 10.5.8.5,10.5.8.6, 10.5.8.7, 10.5.8.8, 10.5.8.9, 10.5.8.10, 10.5.9.1, 10.5.9.2,10.5.9.3, 10.5.9.4, 10.5.9.5, 10.5.9.6, 10.5.9.7, 10.5.9.8, 10.5.9.9,10.5.9.10, 10.5.10.1, 10.5.10.2, 10.5.10.3, 10.5.10.4, 10.5.10.5,10.5.10.6, 10.5.10.7, 10.5.10.8, 10.5.10.9, 10.5.10.10, 10.6.1.1,10.6.1.2, 10.6.1.3, 10.6.1.4, 10.6.1.5, 10.6.1.6, 10.6.1.7, 10.6.1.8,10.6.1.9, 10.6.1.10, 10.6.2.1, 10.6.2.2, 10.6.2.3, 10.6.2.4, 10.6.2.5,10.6.2.6, 10.6.2.7, 10.6.2.8, 10.6.2.9, 10.6.2.10, 10.6.3.1, 10.6.3.2,10.6.3.3, 10.6.3.4, 10.6.3.5, 10.6.3.6, 10.6.3.7, 10.6.3.8, 10.6.3.9,10.6.3.10, 10.6.4.1, 10.6.4.2, 10.6.4.3, 10.6.4.4, 10.6.4.5, 10.6.4.6,10.6.4.7, 10.6.4.8, 10.6.4.9, 10.6.4.10, 10.6.5.1, 10.6.5.2, 10.6.5.3,10.6.5.4, 10.6.5.5, 10.6.5.6, 10.6.5.7, 10.6.5.8, 10.6.5.9, 10.6.5.10,10.6.6.1, 10.6.6.2, 10.6.6.3, 10.6.6.4, 10.6.6.5, 10.6.6.6, 10.6.6.7,10.6.6.8, 10.6.6.9, 10.6.6.10, 10.6.7.1, 10.6.7.2, 10.6.7.3, 10.6.7.4,10.6.7.5, 10.6.7.6, 10.6.7.7, 10.6.7.8, 10.6.7.9, 10.6.7.10, 10.6.8.1,10.6.8.2, 10.6.8.3, 10.6.8.4, 10.6.8.5, 10.6.8.6, 10.6.8.7, 10.6.8.8,10.6.8.9, 10.6.8.10, 10.6.9.1, 10.6.9.2, 10.6.9.3, 10.6.9.4, 10.6.9.5,10.6.9.6, 10.6.9.7, 10.6.9.8, 10.6.9.9, 10.6.9.10, 10.6.10.1, 10.6.10.2,10.6.10.3, 10.6.10.4, 10.6.10.5, 10.6.10.6, 10.6.10.7, 10.6.10.8,10.6.10.9, 10.6.10.10, 10.7.1.1, 10.7.1.2, 10.7.1.3, 10.7.1.4, 10.7.1.5,10.7.1.6, 10.7.1.7, 10.7.1.8, 10.7.1.9, 10.7.1.10, 10.7.2.1, 10.7.2.2,10.7.2.3, 10.7.2.4, 10.7.2.5, 10.7.2.6, 10.7.2.7, 10.7.2.8, 10.7.2.9,10.7.2.10, 10.7.3.1, 10.7.3.2, 10.7.3.3, 10.7.3.4, 10.7.3.5, 10.7.3.6,10.7.3.7, 10.7.3.8, 10.7.3.9, 10.7.3.10, 10.7.4.1, 10.7.4.2, 10.7.4.3,10.7.4.4, 10.7.4.5, 10.7.4.6, 10.7.4.7, 10.7.4.8, 10.7.4.9, 10.7.4.10,10.7.5.1, 10.7.5.2, 10.7.5.3, 10.7.5.4, 10.7.5.5, 10.7.5.6, 10.7.5.7,10.7.5.8, 10.7.5.9, 10.7.5.10, 10.7.6.1, 10.7.6.2, 10.7.6.3, 10.7.6.4,10.7.6.5, 10.7.6.6, 10.7.6.7, 10.7.6.8, 10.7.6.9, 10.7.6.10, 10.7.7.1,10.7.7.2, 10.7.7.3, 10.7.7.4, 10.7.7.5, 10.7.7.6, 10.7.7.7, 10.7.7.8,10.7.7.9, 10.7.7.10, 10.7.8.1, 10.7.8.2, 10.7.8.3, 10.7.8.4, 10.7.8.5,10.7.8.6, 10.7.8.7, 10.7.8.8, 10.7.8.9, 10.7.8.10, 10.7.9.1, 10.7.9.2,10.7.9.3, 10.7.9.4, 10.7.9.5, 10.7.9.6, 10.7.9.7, 10.7.9.8, 10.7.9.9,10.7.9.10, 10.7.10.1, 10.7.10.2, 10.7.10.3, 10.7.10.4, 10.7.10.5,10.7.10.6, 10.7.10.7, 10.7.10.8, 10.7.10.9, 10.7.10.10, 10.8.1.1,10.8.1.2, 10.8.1.3, 10.8.1.4, 10.8.1.5, 10.8.1.6, 10.8.1.7, 10.8.1.8,10.8.1.9, 10.8.1.10, 10.8.2.1, 10.8.2.2, 10.8.2.3, 10.8.2.4, 10.8.2.5,10.8.2.6, 10.8.2.7, 10.8.2.8, 10.8.2.9, 10.8.2.10, 10.8.3.1, 10.8.3.2,10.8.3.3, 10.8.3.4, 10.8.3.5, 10.8.3.6, 10.8.3.7, 10.8.3.8, 10.8.3.9,10.8.3.10, 10.8.4.1, 10.8.4.2, 10.8.4.3, 10.8.4.4, 10.8.4.5, 10.8.4.6,10.8.4.7, 10.8.4.8, 10.8.4.9, 10.8.4.10, 10.8.5.1, 10.8.5.2, 10.8.5.3,10.8.5.4, 10.8.5.5, 10.8.5.6, 10.8.5.7, 10.8.5.8, 10.8.5.9, 10.8.5.10,10.8.6.1, 10.8.6.2, 10.8.6.3, 10.8.6.4, 10.8.6.5, 10.8.6.6, 10.8.6.7,10.8.6.8, 10.8.6.9, 10.8.6.10, 10.8.7.1, 10.8.7.2, 10.8.7.3, 10.8.7.4,10.8.7.5, 10.8.7.6, 10.8.7.7, 10.8.7.8, 10.8.7.9, 10.8.7.10, 10.8.8.1,10.8.8.2, 10.8.8.3, 10.8.8.4, 10.8.8.5, 10.8.8.6, 10.8.8.7, 10.8.8.8,10.8.8.9, 10.8.8.10, 10.8.9.1, 10.8.9.2, 10.8.9.3, 10.8.9.4, 10.8.9.5,10.8.9.6, 10.8.9.7, 10.8.9.8, 10.8.9.9, 10.8.9.10, 10.8.10.1, 10.8.10.2,10.8.10.3, 10.8.10.4, 10.8.10.5, 10.8.10.6, 10.8.10.7, 10.8.10.8,10.8.10.9, 10.8.10.10, 10.9.1.1, 10.9.1.2, 10.9.1.3, 10.9.1.4, 10.9.1.5,10.9.1.6, 10.9.1.7, 10.9.1.8, 10.9.1.9, 10.9.1.10, 10.9.2.1, 10.9.2.2,10.9.2.3, 10.9.2.4, 10.9.2.5, 10.9.2.6, 10.9.2.7, 10.9.2.8, 10.9.2.9,10.9.2.10, 10.9.3.1, 10.9.3.2, 10.9.3.3, 10.9.3.4, 10.9.3.5, 10.9.3.6,10.9.3.7, 10.9.3.8, 10.9.3.9, 10.9.3.10, 10.9.4.1, 10.9.4.2, 10.9.4.3,10.9.4.4, 10.9.4.5, 10.9.4.6, 10.9.4.7, 10.9.4.8, 10.9.4.9, 10.9.4.10,10.9.5.1, 10.9.5.2, 10.9.5.3, 10.9.5.4, 10.9.5.5, 10.9.5.6, 10.9.5.7,10.9.5.8, 10.9.5.9, 10.9.5.10, 10.9.6.1, 10.9.6.2, 10.9.6.3, 10.9.6.4,10.9.6.5, 10.9.6.6, 10.9.6.7, 10.9.6.8, 10.9.6.9, 10.9.6.10, 10.9.7.1,10.9.7.2, 10.9.7.3, 10.9.7.4, 10.9.7.5, 10.9.7.6, 10.9.7.7, 10.9.7.8,10.9.7.9, 10.9.7.10, 10.9.8.1, 10.9.8.2, 10.9.8.3, 10.9.8.4, 10.9.8.5,10.9.8.6, 10.9.8.7, 10.9.8.8, 10.9.8.9, 10.9.8.10, 10.9.9.1, 10.9.9.2,10.9.9.3, 10.9.9.4, 10.9.9.5, 10.9.9.6, 10.9.9.7, 10.9.9.8, 10.9.9.9,10.9.9.10, 10.9.10.1, 10.9.10.2, 10.9.10.3, 10.9.10.4, 10.9.10.5,10.9.10.6, 10.9.10.7, 10.9.10.8, 10.9.10.9, 10.9.10.10, 10.10.1.1,10.10.1.2, 10.10.1.3, 10.10.1.4, 10.10.1.5, 10.10.1.6, 10.10.1.7,10.10.1.8, 10.10.1.9, 10.10.1.10, 10.10.2.1, 10.10.2.2, 10.10.2.3,10.10.2.4, 10.10.2.5, 10.10.2.6, 10.10.2.7, 10.10.2.8, 10.10.2.9,10.10.2.10, 10.10.3.1, 10.10.3.2, 10.10.3.3, 10.10.3.4, 10.10.3.5,10.10.3.6, 10.10.3.7, 10.10.3.8, 10.10.3.9, 10.10.3.10, 10.10.4.1,10.10.4.2, 10.10.4.3, 10.10.4.4, 10.10.4.5, 10.10.4.6, 10.10.4.7,10.10.4.8, 10.10.4.9, 10.10.4.10, 10.10.5.1, 10.10.5.2, 10.10.5.3,10.10.5.4, 10.10.5.5, 10.10.5.6, 10.10.5.7, 10.10.5.8, 10.10.5.9,10.10.5.10, 10.10.6.1, 10.10.6.2, 10.10.6.3, 10.10.6.4, 10.10.6.5,10.10.6.6, 10.10.6.7, 10.10.6.8, 10.10.6.9, 10.10.6.10, 10.10.7.1,10.10.7.2, 10.10.7.3, 10.10.7.4, 10.10.7.5, 10.10.7.6, 10.10.7.7,10.10.7.8, 10.10.7.9, 10.10.7.10, 10.10.8.1, 10.10.8.2, 10.10.8.3,10.10.8.4, 10.10.8.5, 10.10.8.6, 10.10.8.7, 10.10.8.8, 10.10.8.9,10.10.8.10, 10.10.9.1, 10.10.9.2, 10.10.9.3, 10.10.9.4, 10.10.9.5,10.10.9.6, 10.10.9.7, 10.10.9.8, 10.10.9.9, 10.10.9.10, 10.10.10.1,10.10.10.2, 10.10.10.3, 10.10.10.4, 10.10.10.5, 10.10.10.6, 10.10.10.7,10.10.10.8, 10.10.10.9, 10.10.10.10

Additional exemplary formula 1 compound groups include compounds orgenera of compounds named in the groups disclosed below. Theconfigurations of all hydrogen atoms for the following groups are asdefined for the group 1 compounds above.

Group 2 compounds. These compounds are named as defined for group 1compounds, except that R¹⁴ in formula 3 is —OH and R¹⁵ is —H. Thus, thegroup 2 compound named 4.2.2.3 has the structure

Group 3 compounds. These compounds are named as defined for group 1compounds, except that R¹⁴ in formula 3 is —H and R¹⁵ is —OH. Thus, thegroup 3 compound named 4.2.2.3 has the structure

Group 4 compounds. These compounds are named as defined for group 1compounds, except that R¹⁴ and R¹⁵ in formula 3 are both —OH. Thus, thegroup 4 compound named 4.2.2.3 has the structure

Group 5 compounds. These compounds are named as defined for group 1compounds, except that R¹⁴ and R¹⁵ in formula 3 together comprise ═O.Thus, the group 5 compound named 4.2.2.3 has the structure

Group 6 compounds. These compounds are named as defined for group 1compounds, except that R²⁴ in formula 3 is —H, —CH₂OH, —CH₂OC(O)CH₃,—OC(O)CH₃ or —CH₂OC(O)OCH₃. Thus, the group 6 compound named 4.2.2.3 hasthe structure

where R²⁴ is —H, —CH₂OH, —CH₂OC(O)CH₃, —OC(O)CH₃ or —CH₂OC(O)OCH₃.

Group 7 compounds. These compounds are named as defined for group 1compounds, except that R²⁵ in formula 3 is —H, —CH₂OH, —CH₂OC(O)CH₃,—OC(O)CH₃ or —CH₂OC(O)OCH₃. Thus, the group 7 compound named 4.2.2.3 hasthe structure

where R²⁵ is —H, —CH₂OH, —CH₂OC(O)CH₃, —OC(O)CH₃ or —CH₂OC(O)OCH₃.

Group 8 compounds. These compounds are named as defined for group 1compounds, except that the double bond at the 5-6 position is absent,R⁹, R¹⁰ and R¹¹ (as defined for formula 1) are present and are allhydrogen, and R⁹ is in the α-configuration. Thus, the group 8 compoundnamed 4.2.2.3 has the structure

Group 9 compounds. These compounds are named as defined for group 1compounds, except that the double bond at the 5-6 position is absent,R⁹, R¹⁰ and R¹¹ (as defined for formula 1) are present and are allhydrogen, and R⁹ is in the β-configuration. Thus, the group 9 compoundnamed 4.2.2.3 has the structure

Group 10 compounds. These compounds are named as defined for group 1compounds, except that R¹⁴ is —O—C(O)—CH₂NH₂, —O—C(O)—O—CH₃, —O—C(O)—CH₃or —SH. Thus, the group 10 compound named 4.2.2.3 has the structure

where R¹⁴ is —O—C(O)—CH₂NH₂, —O—C(O)—O—CH₃, —O—C(O)—CH₃ or —SH.

Group 11 compounds. These compounds are named as defined for group 1compounds, except that R¹⁵ is —OH, —O—C(O)—O—CH₃, —O—C(O)—CH₃ or —SH.Thus, the group 11 compound named 4.2.2.3 has the structure

where R¹⁵ is —O—C(O)—CH₂NH₂, —O—C(O)—O—CH₃, —O—C(O)—CH₃ or —SH.

Group 12 compounds. Group 12 comprises 11 subgroups of compounds,subgroups 12-1 through group 12-11. These compounds are named as definedfor any compound or genus in any of group 1 through group 11 compounds,except that the R⁵ and R⁶ structures in Table 1 have the followingstructures. 1-Cl, —H; 2-H, —Cl; 3-H, —Br; 4-Br, —H; 5-O—CH₂—C₆H₄—OCH₃,—H; 6-H, —O—CH₂—C₆H₄—OCH₃; 7-O—CH₂—C₆H₄—F, —H; 8-H, —O—CH₂—C₆H₄—F;9-O—C(O)—CH₂—C₆H₅, —OH; 10-OH, —O—C(O)—CH₂—C₆H₅. Thus, the subgroup 12-1and 12-2 compounds named 4.2.2.3 have the structure

subgroup 12-1, compound 4.2.2.3,

subgroup 12-2, compound 4.2.2.3.

Group 13 compounds. Group 13 comprises 11 subgroups of compounds,subgroups 13-1 through group 13-11. These compounds are named as definedfor any compound or genus in any of group 1 through group 11 compounds,except that the R⁵ and R⁶ structures in Table 1 have the followingstructures. 1-H, —H; 2-H, —CCH₃; 3-CCH₃, —H; 4-OH, —CCH₃; 5-CCH₃, —OH;6-H, —CH₃; 7-CH₃, —H; 8-CH₃, —CH₃; 9-C₂H₅, —C₂H₅; 10-C₂H₅, —H. Thus, thegroup 13-1 and 13-2 compounds named 4.2.2.3 have the structure

subgroup 13-1, compound 4.2.2.3,

subgroup 13-2, compound 4.2.2.3.

Other embodiments of the formula 1 and 2 compounds include compoundshaving the formulas 3 and 4

wherein, R¹-R²⁷ are independently chosen and have the definitions givenherein. Exemplary formula 3 and 4 compounds have 0, 1, 2 or 3 doublebonds and a non-hydrogen substituent at 2, 3, 4 or more of R¹,R³,R⁵,R¹¹, R¹³, R¹⁷, R¹⁹, R²⁴ and R²⁵. When three double bonds are present inthe A ring, then R²⁵ is absent. Such embodiments include each of thecompounds groups described above wherein the A ring is aromatic and insuch compounds, only one variable group is present at each carbon atomin the A ring, and the R¹, R³, R⁵ and R⁷ variable groups are as definedin the compound groups given above. Substituents include methyl at R²⁴and R²⁵ and independently selected —OR^(PR) (e.g., —OH),═O, —SR^(PR)(e.g., —SH) or halogen at 2, 3 or more of R¹, R³,R⁵, R¹¹, R¹³, R¹⁷ andR¹⁹, with remaining positions being hydrogen.

In other embodiments the formula 3 compound shown in compound group 1comprises (1) a double bond at the 16-17 position and only R¹⁷ and R¹⁸are present at 16 and 17, (2) a double bond at the 16-17 position andonly R¹⁶ and R¹⁸ are present at 16 and 17, (3) a double bond at the16-17 position and only R¹⁷ and R¹⁹ are present at 16 and 17, (4) adouble bond at the 16-17 position and only R¹⁶ and R¹⁹ are present at 16and 17, (5) a double bond at the 5-6 and 16-17 positions and only R¹⁷and R¹⁸ are present at 16 and 17, (6) a double bond at the 5-6 and 16-17positions and only R¹⁶ and R¹⁸ are present at 16 and 17, (7) a doublebond at the 5-6 and 16-17 positions 5-6 and 16-17 positions and only R¹⁷and R¹⁹ are present at 16 and 17, (8) a double bond at the 5-6 and 16-17positions and only R¹⁶ and R¹⁹ are present at 16 and 17, (9) a doublebond at the 4-5 and 16-17 positions and only R¹⁷ and R¹⁸ are present at16 and 17, (10) a double bond at the 4-5 and 16-17 positions and onlyR¹⁶ and R¹⁸ are present at 16 and 17, (11) a double bond at the 4-5 and16-17 positions 4-5 and 16-17 positions and only R¹⁷ and R¹⁹ are presentat 16 and 17, (12) a double bond at the 5-6 and 16-17 positions and onlyR¹⁶ and R¹⁹ are present at 16 and 17, (13) a double bond at the 1-2 and16-17 positions and only R¹⁷ and R¹⁸ are present at 16 and 17, (14) adouble bond at the 1-2 and 16-17 positions and only R¹⁶ and R¹⁸ arepresent at 16 and 17, (15) a double bond at the 1-2 and 16-17 positions5-6 and 16-17 positions and only R¹⁷ and R¹⁹ are present at 16 and 17,or (16) a double bond at the 1-2 and 16-17 positions and only R¹⁶ andR¹⁹ are present at 16 and 17. In any of these embodiments, a singlevariable group is bonded to ring carbon atoms and the variable group canbe as described in any of the compound groups described above. For thesecompounds, the variable groups at the 1, 2, 4, 6, 11 and 12 positionsmay comprise one, two or three moieties other than hydrogen, e.g.,optionally substituted alkyl, optionally substituted alkoxy, optionallysubstituted alkylaryl, an ester, an ether, a thioether, a thioester, anoptionally substituted heterocycle, or an optionally substitutedmonosaccharide, while the remainder of the variable groups at the 1, 2,4, 6, 11 and 12 positions are hydrogen.

In some embodiments, when one or more of R¹-R²⁸ is a protected moiety,e.g., —OR^(PR), —SR^(PR), —N(R^(PR))₂, the R^(PR) protecting group,together with the atom to which it is linked, comprises an ester, athioester, a phosphoester, a phosphonoester, a sulfite ester, a sulfateester, an amide, an amino acid, a peptide, an ether, a thioether, anacyl group, a carbonate, a carbamate, a sulfonamide, an optionallysubstituted alkyl group, an optionally substituted alkenyl group, anoptionally substituted alkynyl group, an optionally substituted arylmoiety, an optionally substituted heteroaryl moiety, an optionallysubstituted monosaccharide, an optionally substituted oligosaccharide, anucleoside, a nucleotide, an oligonucleotide or a polymer.

In all of the embodiments of the formula 1 or formula 2 compoundsdescribed herein, the variable groups are in the α, β or αβconfiguration, unless otherwise specified. Esters and thioesters at one,two or more variable groups, e.g., at 1, 3, 6, 7 or 17, may comprise asaturated or unsaturated, normal or branched fatty acid, typicallycomprising about 4 to about 20 carbon atoms. Such fatty acids, ifunsaturated may comprise one, two or more double bonds or one or twotriple bonds. Exemplary fatty acids include one having the structureCH₃—(CH₂)₃₋₁₈—COOH, CH₃—(CH₂)₁₋₈—CH═CH—(CH₂)₁₋₈—COOH,CH₃—(CH₂)₂₋₆—CH═CH—(CH₂)₂₋₆—COOH andCH₃—(CH₂)₁₋₅—CH═CH—(CH₂)₂₋₄—CH═CH—(CH₂)₁₋₅—COOH. The double bond in thefatty acids can be in the cis, trans or cis and trans configurations andthey are optionally substituted with one, two or more substituents asdescribed for esters, e.g., with —O—, —OH, —S— or —SH.

Exemplary synthesis methods. By way of exemplification and notlimitation, the following methods are used to prepare the one or more ofthe compounds disclosed herein. Starting materials or straightforwardvariations of the schemes are found, e.g., in the following citations,which are all incorporated herein by reference: U.S. Pat. Nos.4,602,008, 4,989,694, 5,001,119, 5,175,154, 5,571,795, 5,627,270,5,681,964, 5,714,481, 5,744,453, 5,939,545, 5,939,570, 5,962,442,5,962,443, 5,994,568; international publication numbers WO 9408588, WO9508558, WO 9508559, WO 9638466, WO 9809450; and European patentapplications EP 232788, EP 430078.

Scheme 1. Exemplary formula 1 compounds are prepared as shown in theschemes below. For the structures shown in scheme 1, R⁵-R⁹ are asdefined for formula 1 compounds. Thus, when R²⁴ and R²⁵ are both —CH₃ inthe β-configuration, H at the 9 and 14 positions are in theα-configuration, acetate at the 3-position is in the β-configuration,and H at the 8 position is in the β-configuration, the first compound inscheme 1 is DHEA acetate. The acetate groups at the 3, 7, 16, 17 orother positions in this scheme and in other schemes disclosed herein mayindependently be other ester moieties as described herein, e.g., C₂₋₅₀esters including —C(O)—(CH₂)₀₋₄—(CF₂)₀₋₄—CF₃, including —C(O)—CF₃,—C(O)—C₂₋₂₉ optionally substituted alkyl, —C(O)—CH₂—C₂₋₂₈ optionallysubstituted alkenyl, —C(O)—CH₂—C₂₋₂₈ optionally substituted alkynyl,—C(O)—(CH₂)₀₋₆-optionally substituted phenyl, or—C(O)—(CH₂)₀₋₆-optionally substituted heterocycle or other organicmoieties as disclosed herein or in the cited references.

Typical substituents for these organic moieties are as described herein,e.g., one, two, three or more independently selected —O—, ═O, optionallyprotected hydroxyl, —S—, optionally protected thiol, —NH—, optionallyprotected —NH₂, optionally protected —C(O)OH, —C(O)—NH—, —C(O)—NH₂,—NH₂—C(O)—H, —NH₂—C(O)—C₀₋₄H₁₋₉, —NH₂—C(O)—O—C₀₋₄H₁₋₉, —CN, —NO₂, —N₃ orhalogen. Reactive groups are protected as needed, e.g., ═O would usuallybe protected in the LiCR reaction that is used to generate compound 1 inscheme 1 below.

Scheme 2. Compounds of formula 2A are prepared from structure Acompounds shown in scheme 1 using the last two steps of Scheme 1: (1)dibromantin, (2) LiBr, (3) Li—C—R, where R is CR^(A) and R^(A) is —H or—C₁₋₁₂ optionally substituted alkyl. When H at the 9 and 14 positionsare in the 1-configuration and H at the 8 position is in theβ-configuration the first compound in scheme 1 is DHEA acetate. Typicalsubstituents for the R^(A) alkyl moiety includes one, two or moreindependently selected —O—, optionally protected ═O, optionallyprotected hydroxyl, —S—, optionally protected thiol, —NH—, optionallyprotected —NH₂, optionally protected —C(O)OH, —C(O)—NH—, —C(O)—NH₂,—NH₂—C(O)—H, —NH₂—C(O)—CO₄H₁₉, —NH₂—C(O)—O—C₀₋₄H₁₋₉, —CN, —NO₂, —N₃ orhalogen.

Scheme 3. The allylic bromination at C-7 is accomplished essentially asshown in Scheme 1. R and R^(A) are as defined in Schemes 1 and 2.

Scheme 4. The addition of lithium reagent (lithium acetylide when R is—CH) to the 17-position >C═O in the presence of the bromide at C-16results in epoxide formation or in a pinacol rearrangement.Alternatively, compounds without of structure 3 can be dehydrated bymild acid catalysis to form compounds of formula 4 by treatment of thealkene with Br₂, H₂O. R and R^(A) are as defined in Schemes 1 and 2.

Scheme 5. Sodium borohydride gives a mixture of epimers at C-7, whichmay be separated by standard methods, e.g., HPLC, TLC or columnchromatography. To obtain the pure 7α-OH compound, allylic brominationfollowed by hydrolysis is accomplished, e.g., essentially as describedin Schemes 1 and 3.

Scheme 6. Formula 6 compounds are prepared by treatment of the acetatewith lithium acetylide as in Schemes 1, 2, 3 or 4. R and R^(A) are asdefined in Schemes 1 and 2.

Scheme 7. Formula 7 compounds are prepared from the 3-acetate withreagents described in Schemes 1 and 4. R and R^(A) are as defined inSchemes 1 and 2.

Scheme 8. Formula 8 compounds are prepared from the formula A compoundsby sodium borohydride reduction at C-17 followed by acetylation.

Scheme 9. The starting material is made using reactions described inSchemes 1 and 3.

Scheme 10. Reduction and acetylation at C-3 and hydrolysis and oxidationat C-17 will allow formula 10a and 10b compounds to undergofunctionalization as shown in Schemes 1-9 at C-3, C-16 and C-17. The7-oxo acetate can be substituted for the formula A compound 3-acetateand functionalization at C-3, C-16 and C-17 is achieved similarly for7-oxo compounds using the reactions shown in schemes 1-9.

Treatment of 10a with LDA, followed by alkylation of the enolate allowsintroduction of side chains, which may be, e.g., C1-C20 alkyl (methyl,ethyl), C1-C20 alkenyl (CH₂═CH—(CH₂)₀₋₆—), benzyl,—(CH₂)₁₋₄—O—(CH₂)₀₋₄—CH₃.

Schemes 1-9 show the introduction of the hydroxyl function at thepositions shown. Methods to convert hydroxyl to other functional groupsare accomplished essentially as described, e.g., in the references citedherein. For example, esters, of formula 1-10c compounds, such as—O—C(O)—R^(B) where R^(B) is a C₁₋₅₀ organic moiety, are prepared fromthe steroid alcohol by treatment with the appropriate acid anhydride oracid chloride (R^(B)—C(O)—Cl) to form any desired ester. Ethers, such as—O—R^(B), are prepared from alcohols by formation of the alkaline metalalkoxide (Na⁺ or K⁺) followed by treatment with a primary or secondaryiodide (R^(B)—I). Thionoesters, R^(B)—C(S)—O—, are prepared by treatingthe R^(B)—C(O)—O— ester with Lawesson's reagent.

Sulfates, NaO—S(O)(O)—O—, R^(B)—O—S(O)(O)—O—, e.g.,CH₃(CH₂)₀₋₁₈—S(O)(O)—O—, are prepared by treatment of alcohols withchlorosulfonic acid followed by NaOH or alternatively by oxidation ofsulfites using KMnO₄. If the alkyl (e.g., methyl) ester is desiredalkylchloro-sulfonate (methylchloro-sulfonate) can be used. SulfitesHO—S(O)—O— and ammonium salts NH₄O—S(O)—O, or R^(B)O—S(O)—O— esters(e.g., CH₃O—S(O)—O—) are prepared by standard methods. The ammoniumsalts are prepared by treatment of alcohols with ammonia and sulfurdioxide. The esters such as alkyl, alkenyl and alkynyl esters (e.g.,methyl ester) are obtained when alcohols are treated withalkylchlorosulfite (e.g., methycholorosulfite), alkenylchlorosulfite oralkynylchlorosulfite in the presence of a suitable base such astriethylamine. Phosphoesters, R^(B)O—P(OR^(PR))(O)—O— are prepared bytreating the alcohol with diethylchlorophosphate in the presence ofNa₂CO₃. Alternatively, if the alcohol is treated with phosphoric aciddiesters in the presence of triphenylphospine (PPh₃) anddiethylazodicarboxylate (DEAD) the corresponding triesters are formedwith inversion (Mitsunobu reaction).

Phosphothioesters, R^(B)O—P(SR^(PR))(O)—O— are generated by treatment ofalcohols with the monothio analog of diethylchlorophosphate as describedfor phosphoesters yielding the phosphothioesters. Carbonates,R^(B)O—C(O)—O— are generated from the corresponding steroid alcoholusing the chloroformate (R^(B)—C (O)—Cl), e.g., C₁₋₂₀ alkyl, alkenyl oralkynyl chloroformates (e.g. CH₃(CH₂)₀₋₅—C(O)Cl). Carbamates,R^(B)—NH—C(O)—O— are made from steroid alcohols by treatment withisocyanates (R^(B)N═C═O) or NaOCN in the presence of trifluroroaceticacid. Amino acid esters, ZNX—CHY—C(O)—O— are generated by coupling thesteroid alcohol with the acid chloride of the N—protected amino acid.

Oxidation of hydroxyl groups that are linked to the steroid nucleus isused to obtain ketones and related functionalities. For example,conversion of alcohols to ketones can be achieved using a variety ofoxidizing agents such as CrO₃ in AcOH, or pyridinium chlorochromate,pyridinium dichromate or oxalyl chloride with triethylamine (Swernoxidation). Thioketones (═S) are prepared by treating ketones withLawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide;commercially available from Aldrich). Thioacetals, —C(SR^(B))(SR^(B))—,are prepared from ketones (—C(O)—) by treatment with R^(B)—SH thiolsunder acid catalysis conditions (e.g., HCl). Phosphonoesters,RO—P(OR^(PR))(O)—, are generated by addition of the phosphorus aciddiester to ketones in the presence of KF to yield hydroxyphosphonoesters. One may optionally remove the hydroxy group using adehydration and hydrogenation sequence.

Substitution of hydroxyl groups is used to generate a number offunctionalities. For example, thiols, —SH, are prepared from alcohols byconversion of the alcohol with inversion to the bromide using PBr₃.Treatment of the bromide with thiourea followed by NaOH gives the thiol.Thioethers, R^(B)—S—, are prepared from thiols by treatment with NaOHand the required halide, e.g., alkyl halide. Alternatively, alcoholderivatives like tosylates or mesylates can be displaced by thiolateanions, R^(B)—S—, to yield the thioether. Thioesters, R—C(O)—S—, areprepared by treating the tosylate (mesylate) of the alcohol with thesodium salt of the thioacid.

Substitution of hydroxyl groups can be used to generate both esters,R^(B)O—C(O)—, and amides, NHR^(B)—C(O)—, linked to the steroid at carbonatoms. For amides and amines, R^(B) is —H, a protecting group or a C₁₋₅₀organic moiety. These are synthesized from the steroid bromide withinversion by displacement with NaCN. The cyanide group can be hydrolyzedto the amide or the acid. The acid is esterified or treated by standardpeptide coupling reactions with an O-protected amino acid in thepresence of a suitable carboxyl activating agents such asdicyclohexylcarbodiimide (DCC) to form steroid —C(O)—NH—CHY—C(O)—OR,where Y is the side chain of an amino acid or a C1-C10 organic moietyand R is a protecting group (or hydrogen when deprotected).

Amines and derivatives of amines, e.g., R^(B)NH—, R^(B)—C(O)NH—,R^(B)OC(O)—NH— or R^(B)O—C(O)—CHR^(B)—NH— linked to steroid carbonatoms, are typically prepared by standard methods. For example, amines(NH₂-steroid) are generally prepared using the Hoffmann rearrangement(Br₂, NaOH) from the amide (NH₂—C(O)-steroid) or the Curtiusrearrangement (NaN₃) from the acid chloride of the steroid. The R^(B)substituent can subsequently be introduced by alkylation. Steroidalcohols can be used as starting materials under standard Mitsunobuconditions (PPh₃, DEAD) to yield N-Boc sulfonamides usingN-(t-butoxycarbonyl)-p-toluenesulfonamide. One can selectively removeeither protecting group. Treatment with trifluoroacetic acid affords thesulfonamide (R^(B)—S(O)(O)—NH-steroid). Alternatively, sodiumnapthalenide deprotects to give the N-Boc compound. Amines (NH₂-steroid)can be converted to amides (R^(B)NH—C(O)-steroid) using acyl chlorides(R^(B)—C(O)—Cl). Treatment with ethyl chloroformate gives theN-carbamate (R^(B)O—C(O)—NH-steroid). The amine (NH₂-steroid) can bealkylated with an α-bromoester (R^(B)—C(O)—CHY—NH₂) to yield the aminoacid substituted steroid (R^(B)—O—C(O)—CHY—NH-steroid).

Where reactions such as substitutions give a product mixture, thedesired intermediate is optionally separated from other products or atleast partially enriched (e.g., enriched at least about 10-fold, usuallyat least about 50-100-fold) from other products before subsequentreactions are conducted. Substitution at steroid carbon atoms willgenerally proceed with greatest efficiency at the 3-position, which isrelatively sterically unhindered and C-17 is generally somewhat lessaccessible than the C-3 position. The relative reactivities of the C-3,C-7, C-17 and C-16 positions allows one to use their reactivities tocontrol the sequential introduction of different functional groups intothe same steroid molecule. Also, groups, such as hydroxyl at morereactive positions, C-3 or C-17, may be sequentially protected ordeprotected to allow introduction of functional groups at otherpositions, such as C-7 or C-16.

Polymers such as PEG are linked to the compounds essentially asdescribed above. For example, PEG 200 or PEG 300 is linked to thesteroid at the 3, 7, 16, 17 or other positions by an ether linkage(PEG-O-steroid) using a PEG alkoxide (PEG-ONa), to displace the steroidbromide. Alternatively, PEG-Br can be treated with the steroid alkoxide.Polyethylene glycol esters such as those described in U.S. Pat. No.5,681,964 can also be prepared using a suitable formula 1 compound andthe methods described therein. Monosaccharides or polysaccharides andoligonucleotides are linked to steroid hydroxyl groups using knownmethods, see e.g., U.S. Pat. No. 5,627,270.

Scheme 11. Formula 1 or 2 compounds that contain an organic moiety thatis linked to the 1 position are prepared essentially as follows. Theallylic bromination reaction to generate 11 may utilize any suitablereagent, e.g., N-bromosuccinimide (“NBS”) to yield the 1-bromoderivative. This intermediate is treated with zinc to yield thealkylated derivative 12. Organic moieties are introduced into the 1position using a corresponding reagent, e.g., (R³⁵)₂CuLi, where R³⁵ is aC1-C25 organic moiety that may comprise 1, 2, 3, 4 or more substituents,e.g., —O—, —S—, —NH—, —OR^(PR), protected ketone (e.g., ethylene ketal),—SR^(PR) or —N(R^(PR))₂. In other embodiments, R³⁵ is R¹. Thus, when R³⁵is methyl, a methyl group is introduced into the 1 position, or when R³⁵is —CH₂—OR^(PR), the —CH₂—OR^(PR) group is introduced into the 1position. Compound 12 is converted to the 17 hydroxyl derivative 13 byhydrolysis using standard methods, e.g., treatment with sodium carbonatein methanol. The compound 15 is converted to the 17-hydroxy derivativeby reduction of the ketone, e.g., using LiBH₄ or NaBH₄ in ethanol or bycatalytic hydrogenation with H₂/Ni, H₂/Pt or H₂/Pd. Catalytichydrogenation will also result in reduction of the double bond in 12,13, 14 or 15. Alternatively, a hydroxyl at both the 3 and 17 positionsis obtained by reducing the ketone in compound 12 and removing theacetate group or by directly reducing the 3 ketone in compound 13.

Scheme 12. Formula 1 or 2 compounds that contain a hydroxyl or etherthat is linked to the 1 position are prepared essentially as follows. Ahydroxyl is introduced into the 1 position by oxidation of a suitablestarting material using alkaline hydrogen peroxide to obtain the epoxide16. The compound 16 is converted to the 1-hydroxyl derivative bytreatment, e.g., with excess lithium metal and excess ammonium chloridein NH₄-THF (1:1) at reflux to give 17. The ketal group is hydrolyzed togive the 17 ketone. The hydroxyl group at 1 is optionally furtherconverted to other moieties essentially as described above.

Scheme 13. Formula 1 or 2 compounds that contain an an organic moietythat is linked to the 2 position are prepared essentially as follows.Organic moieties are introduced into the 2 position using acorresponding reagent, e.g., (R³⁵)₂CuLi, where R³⁶ is a C₁-C₂₅ organicmoiety that may comprise 1, 2, 3, 4 or more substituents, e.g., —O—,—S—, —NH—, —OR^(PR), protected ketone (e.g., ethylene ketal), —SR^(PR)or —N(R^(PR))₂. In other embodiments, R³⁶ is R³. Thus, when R³⁶ ismethyl, a methyl group is introduced into the 2 position, or when R³⁶ is—CH₂—OR^(PR), the —CH₂—OR^(PR) group is introduced into the 2 position.The starting material 18 is testosterone when R²⁴ and R²⁵ are bothmethyl. The compound 18 is alkylated using an alkylating agent such asthe iodide R³⁶1 in the presence of a strong base such as lithiumdiisopropylamide (“LDA”), n-butyllithium sodium t-pentoxide or (C₂H₅)₂Nito give R³⁶ bonded to the steroid in the α and β configurations. The2β-R³⁶ group is epimerized to the 2α configuration using a strong base,e.g., a sodium alkoxide such as sodium methoxide in an alcohol such asmethanol. Alternatively the two epimers are at least substantiallyseparated by routine methods.

Other formula 1 and 2 compounds are prepared using methods similar toe.g., those described herein or in the cited references.

The following numbered embodiments further exemplify the invention andsome of its aspects and related subject matter.

1. A method to treat or prevent an androgen responsive disease, e.g.,prostate cancer or breast cancer in a subject comprising administeringto a subject an effective amount of a compound of formula 1 or formula2.

2. The method of embodiment 1 wherein the subject is a human.

3. The method of embodiments 1 or 2 wherein the formula 1 compound is aderivative of 1, 3, 5(10)-estratriene-17α-ethynyl-3β,17β-diol,17α-ethynyl-androstene-3β,17β-diol,3β,17β-dihydroxy-androst-5-en-16-one,3β,-methylcarbonate-androst-5-en-7,17-dione, wherein the derivativecomprises 1, 2, 3, 4, 5 or 6 independently selected moieties selectedfrom an a thioester, a thioether, a carbonate, a carbamate, asulfonamide, halogen, a monosaccharide, a disaccharide, anoligosaccharide, an amino acid or a peptide.

4. The method of any of embodiments 1-3 wherein the formula 1 or formula2 compound is present in a composition that comprises a pharmaceuticallyacceptable carrier.

5. The method of any of embodiments 1-4 wherein a therapeutic agent (ora therapeutic treatment) is present in the assay system or in thesubject, wherein the agent is optionally selected from an effectiveamount of one or more of the group consisting of hydroxyflutamide,leuprolide, megesterol, diethylstilbesterol, aminoglutethimide,spironolactone, tamoxifen, cyproterone acetate, bicalutamidedoxorubicin, cisplatin, estramustine phosphate, hydroxyurea,cyclophosphamide, cyclophosphamide dacarbazine (DITC), procarbazine,semustine (methyl-CCNU), methotrexate, 5-fluorouracil or streptozocin orradiation therapy.

6. The method of embodiment 5 wherein the therapeutic agent ishydroxyflutamide, cyproterone acetate or bicalutamide.

7. The method of any of embodiments 1-6 wherein the formula 1 or formula2 compound comprises 1, 2, 3 or 4 moieties independently selected from—OH, ═O, —SH, ═S, —NH₂, halogen, ═CH₂, ═NOH, ═NOC(O)CH₃,—O—C(O)—(CH₂)_(m)—(CF₂)_(n)—CH₃, —O—C(O)—(CH₂)_(m)—(CF₂)_(n)—CF₃,—O—C(O)—(CH₂)_(m)—(CF₂)_(n)—CH₂F, —O—C(O)—O—(CH₂)_(m)—(CF₂)_(n)—CH₃,O—C(O)—O—(CH₂)_(m)—(CF₂)_(n)—CF₃, —O—C(O)—O—(CH₂)_(m)—(CF₂)_(n)—CH₂F,—O—C(O)—NH—(CH₂)_(m)—(CF₂)_(n)—CH₃, —O—C(O)—NH—(CH₂)_(m)—(CF₂)_(n)—CF₃,—O—C(O)—NH—(CH₂)_(m)—(CF₂)_(n)—CH₂F (where m is 1, 2, 3, 4, 5, 6, 7, 8,9 or 10, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, usually n is 0),—CH(CH₃)—(CH₂)₂—C(O)NH—CH₂COOH, —CH(CH₃)—(CH₂)₂—C(O)NH—CH₂SO₃H,—OSi(CH₃)₂C(CH₃)₃, —C(OH)═CHCH₃, ═CH(CH₂)₀₋₁₅CH₃, —(CH₂)₀₋₁₄—CH₂F,—(CH₂)₀₋₁₄—CH₂Cl, —(CH₂)₀₋₁₄—CH₂Br, —(CH₂)₀₋₁₄—CH₂I,—(CH₂)₂₋₁₀—O—(CH₂)₀₋₄—CH₃, —(CH₂)₂₋₁₀—S—(CH₂)₀₋₄—CH₃,—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄—CH₃, —O—(CH₂)₀₋₁₄—CH₂F, —O—(CH₂)₀₋₁₄—CH₂Cl,—O—(CH₂)₀₋₁₄—CH₂Br, —O—(CH₂)₀₋₁₄—CH₂I, —O—(CH₂)₂₋₁₀—O—(CH₂)₀₋₄—CH₃,—O—(CH₂)₂₋₁₀—S—(CH₂)₀₋₄—CH₃, —O—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄—CH₃,—O—C(O)—(CH₂)₀₋₁₄—CH₂F, —O—C(O)—(CH₂)₀₋₁₄—CH₂Cl,—O—C(O)—(CH₂)₀₋₁₄—CH₂Br, —O—C(O)—(CH₂)₀₋₁₄—CH₂I,—O—C(O)—(CH₂)₂₋₁₀—O—(CH₂)₀₋₄—CH₃, —O—C(O)—(CH₂)₂₋₁₀—S—(CH₂)₀₋₄—CH₃,—O—C(O)—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄—CH₃, —O—C(S)—(CH₂)₀₋₁₄—CH₂F,—O—C(S)—(CH₂)₀₋₁₄—CH₂Cl, —O—C(S)—(CH₂)₀₋₁₄—CH₂Br,—O—C(S)—(CH₂)₀₋₁₄—CH₂I, —O—C(S)—(CH₂)₂₋₁₀—O—(CH₂)₀₋₄—CH₃,—O—C(S)—(CH₂)₂₋₁₀—S—(CH₂)₀₋₄—CH₃, —O—C(S)—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄—CH₃,—(CH₂)₀₋₁₆NH₂, —(CH₂)₀₋₁₅CH₃, —(CH₂)₀₋₁₅CN, —(CH₂)₀₋₁₅CH═CH₂,—(CH₂)₀₋₁₅NHCH(O), —(CH₂)₀₋₁₆NH—(CH₂)₀₋₁₅CH₃, —(CH₂)₀₋₁₅CCH,—(CH₂)₀₋₁₅OC(O)CH₃, —(CH₂)₀₋₁₅OCH(OH)CH₃, —(CH₂)₀₋₁₅C(O)OCH₃,—(CH₂)₀₋₁₅C(O)OCH₂CH₃, —(CH₂)₀₋₁₅C(O)(CH₂)₀₋₁₅CH₃,—(CH₂)₀₋₁₅C(O)(CH₂)₀₋₁₅CH₂OH, —O(CH₂)₁₋₁₆NH₂, —O(CH₂)₁₋₁₅CH₃,—O(CH₂)₁₋₁₅CN, —O(CH₂)₁₋₁₅CH═CH₂, —O(CH₂)₁₋₁₅NHCH(O),—O(CH₂)₁₋₁₆NH—(CH₂)₁₋₁₅CH₃, —O(CH₂)₁₋₁₅CCH, —O(CH₂)₁₋₁₅OC(O)CH₃,—O(CH₂)₁₋₁₅OCH(OH)CH₃, —O(CH₂)₁₋₁₅C(O)OCH₃, —O(CH₂)₁₋₁₅C(O)OCH₂CH₃,—O(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₃, —O(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₂OH,—OC(O)(CH₂)₁₋₁₆NH₂, —OC(O)(CH₂)₁₋₁₅CH₃, —C(O)O(CH₂)₁₋₁₅CN,—C(O)O(CH₂)₁₋₁₅CH═CH₂, —OC(O)(CH₂)₁₋₁₅NHCH(O),—OC(O)(CH₂)₁₋₁₆NH—(CH₂)₁₋₁₅CH₃, —OC(O)(CH₂)₁₋₁₅CCH,—OC(O)(CH₂)₁₋₁₅OC(O)CH₃, —OC(O)(CH₂)₁₋₁₅OCH(OH)CH₃,—OC(O)(CH₂)₁₋₁₅C(O)OCH₃, —OC(O)(CH₂)₁₋₁₅C(O)OCH₂CH₃,—OC(O)(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₃, —OC(O)(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₂OH,—C(O)—O—(CH₂)_(m)CH₃ (where m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10),—(CH₂)_(m)—C(O)OH (where m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10),phosphoenolpyruvate, D-glucosamine, glucholic acid, glucuronic acid,pantothenic acid, pyruvic acid, glucose, fructose, mannose, rhamnose,fucose, sucrose, lactose, glycerol, 3-phosphoglycerate, glycine,alanine, phenylalanine, glutamic acid, lysine, threonine, proline and/or4-hydroxyproline

8. The method of embodiment 7 wherein (a) R²⁴ is —CH₂OH,—CH₂—O—C(O)(CH₂)₁₋₁₆NH₂, —OC(O)(CH₂)₁₋₁₅CH₃ or —OC(O)(CH₂)₁₋₁₅CH₂OH, or(b) R²⁵ is —CH₂OH, —CH₂—O—C(O)(CH₂)₁₋₁₆NH₂, —OC(O)(CH₂)₁₋₁₅CH₃ or—OC(O)(CH₂)₁₋₁₅CH₂OH, or (c) R¹ is —OH, —SH, —NH₂, a halogen,—O—C(O)—CH₃, or —O—C(O)—C₂H₅, or (d) R¹ and R² together are ═O, ═S,═CH₂, ═CHCH₃, ═NOH, ═NOC(O)CH₃, or they are both —OH, or a halogen, or(e) R³ is —OH, —SH, —NH₂, a halogen, —O—C(O)—CH₃, or —O—C(O)—C₂H₅, or(f) R³ and R⁴ together are ═O, ═S, ═CH₂, ═CHCH₃, ═NOH, ═NOC(O)CH₃, orthey are both —OH, or a halogen, or (g) R⁷ is —OH, —SH, —NH₂, a halogen,—O—C(O)—CH₃, or —O—C(O)—C₂H₅, or (h) R⁷ and R⁸ together are ═O, ═S,═CH₂, ═CHCH₃, ═NOH, ═NOC(O)CH₃, or they are both —OH, or a halogen, or(i) R¹⁰ is —OH, —SH, —NH₂, a halogen, —O—C(O)—CH₃, or —O—C(O)—C₂H₅, or(j) R¹⁰ and R¹¹ together are ═O, ═S, ═CH₂, ═CHCH₃, ═NOH, ═NOC(O)CH₃, orthey are both —OH, or a halogen, or (k) R¹⁴ is —OH, —SH, —NH₂, ahalogen, —O—C(O)—CH₃, or —O—C(O)—C₂H₅, or (I) R¹⁴ and R¹⁵ together are═O, ═S, ═CH₂, ═CHCH₃, ═NOH, ═NOC(O)CH₃, or they are both —OH, or ahalogen, or (m) R¹⁶ is —OH, —SH, —NH₂, a halogen, —O—C(O)—CH₃, or—O—C(O)—C₂H₅, or (n) R¹⁶ and R¹⁷ together are ═O, ═S, ═CH₂, ═CHCH₃,═NOH, ═NOC(O)CH₃, or they are both —OH, or a halogen, or (o) R²⁰ is —OH,—SH, —NH₂, a halogen, —O—C(O)—CH₃, or —O—C(O)—C₂H₅, or (p) R²⁰ and R²¹together are ═O, ═S, ═CH₂, ═CHCH₃, ═NOH, ═NOC(O)CH₃, or they are both—OH, or a halogen, or (q) R²² is —OH, —SH, —NH₂, a halogen, —O—C(O)—CH₃,or —O—C(O)—C₂H₅, or (r) R²² and R²³ together are ═O, ═S, ═CH₂, ═CHCH₃,═NOH, ═NOC(O)CH₃, or they are both —OH, or a halogen, or (s) R²⁴ is —OH,—SH, —NH₂, a halogen, —O—C(O)—CH₃, or —O—C(O)—C₂H₅, or (t) R²⁴ and R²⁸together are ═O, ═S, ═CH₂, ═CHCH₃, ═NOH, ═NOC(O)CH₃, or they are both—OH, or a halogen, or (u) R²⁶ is —OH, —SH, —NH₂, a halogen, —O—C(O)—CH₃,or —O—C(O)—C₂H₅, or (v) R²⁶ and R²⁷ together are ═O, ═S, ═CH₂, ═CHCH₃,═NOH, ═NOC(O)CH₃, or they are both —OH, or a halogen.

9. A product produced by the process of contacting a formula 1 or aformula 2 compound with one or more carriers and storing the product forat least about 3 months under ambient conditions in a sealed container.

10. A kit comprising a formula 1 or a formula 2 compound, a containercomprising unit dosage or multiple dosage forms of the formula 1 or 2compound and a label comprising one or more of (1) directions fortherapeutic use of the formula 1 or 2 compound, (2) counterindicationsor toxicities for the formula 1 or 2 compound and (3) information aboutthe formula 1 or 2 compound's structure or the formulation that containsthe formula 1 or 2 compound.

11. A method comprising administering to a subject having an androgenresponsive condition such as benign prostatic hyperplasia, prostatecancer or breast cancer an effective amount of a compound selected fromthe compounds or groups of compounds selected from compounds named inany compound groups described herein.

12. The method of embodiment 11, wherein one or more of the symptoms ofbenign prostatic hyperplasia, prostate cancer or breast cancer areameliorated or wherein any undesired cell proliferation or diseaseprogression associated with benign prostatic hyperplasia, prostatecancer or breast cancer is reduced or delayed.

13. A compound having formula 1 or formula 2.

14. A composition comprising a formula 1 or formula 2 compound and apharmaceutically acceptable carrier.

15. Use of a compound of formula 1 or 2 for the manufacture of amedicament for use to treat or prevent an androgen responsive disease ina subject, or to ameliorate one or more symptoms thereof, e.g., in amammal or a human.

16. The method of embodiment 15 wherein the androgen responsive diseaseis prostate cancer, benign prostatic hyperplasia or breast cancer.

17. A kit comprising a formulation that comprises a unit dosage or amultiple dosage comprising a formula 1 or a formula 2 compound, e.g., acompound in any compound group or embodiment disclosed herein, and oneor more excipients wherein the formulation is dispensed in a suitablecontainer, wherein the kit further comprises a label that providesinformation about one or more of (1) the formula 1 or 2 compound'schemical structure, (2) any recommended dosing regimen, (3) any adverseeffects of administering the formula 1 or 2 compound to a subject thatare required to be disclosed and (4) the amount of the formula 1 or 2compound that is present in each unit dose or in the entire container.

18. A product produced by the process of contacting a formula 1compound, e.g., a compound in any compound group or embodiment disclosedherein, and an excipient.

19. The method of embodiment 1 wherein the compound of formula 1 or 2 isadministered to the subject on an intermittent basis, e.g., dosing for1, 2, 4, 5, 7, 10 or more consecutive days, followed by no dosing for atleast about 5-180 days, followed by dosing again.

20. The method of embodiment 20 herein the compound of formula 1 or 2 isadministered every other day for at least about 3-45 days, followed byat least about 3-180 days of not dosing the subject, optionally followedby another course of administration.

All references cited herein are incorporated herein by reference intheir entirety.

The following examples further illustrate the invention and are notintended to limit it in any manner.

EXAMPLE 1 AR Activity Assay

One biological function of the AR is to act as a transcription factor,which can modulate transcription of target genes. AED,5α-dihydrotestosterone (DHT), 17β-estradiol (E2), and progesterone werepurchased from Sigma. Ethynyl derivatized steroids were purchased fromSteraloids. The plasmid pSG5-wild-type AR (pSG5) and mouse mammaliantumor virus (MMTV)-chloramphenicol acetyltransferase (CAT) wereconstructed as described (6). The numbers in parentheses, e.g., (6) inthe preceding sentence, refer to the references listed in the referencesection below. Other steroid compounds, were synthesized using routineprotocols and others have been described (19, 20). The human prostatecancer cell line, PC-3, and human breast cancer cell line, MCF-7, weremaintained in Dulbecco's modified eagles medium (DMEM) containing 10%fetal calf serum. DNA transfection and CAT assays were performedessentially as described (4, 6, 7). Briefly, 4×10⁵ cells were plated on60 mm dishes 24 h before transfection, and the medium was changed toDMEM (without phenol red) with 10% charcoal-stripped fetal calf serum 1hour before transfection. The cells were transfected using the calciumphosphate precipitation method. The total amount of DNA was adjusted to8.5 μg with pSG5 in each transfection assay. After transfecting thecells for 24 hours, the transfection medium was removed, fresh DMEM wasadded and steroids were added. The cells were then incubated in DMEMwith steroids for 24 hours. After incubation, the cells were harvestedand whole cell extracts were used for CAT assay. Transfection efficiencywas normalized by cotransfection with a β-galactosidase vector, whichacted as an internal control. The CAT enzyme activity was quantitated byphosphor imager according to the manufacturer's instructions (MolecularDynamics).

compound compound number name 0 7-oxo-dehydroepiandrosterone 117α-ethynyl-17β-hydroxy-4-estrene-3-one 217α-ethynyl-17β-hydroxy-4-estrene-3-one 317α-ethynyl-17β-hydroxy-5(10)-estrene-3-one 41,3,5(10)-estratriene-17α-ethynyl-3β,17β-diol 5androst-5-ene-3β,11β,17β-triol 6 17α-ethynyl-androst-5-ene-3β,17β-diol 717α-ethynyl-17β-hydroxy-4-androsten-3-one 83β,17β-dihydroxy-androst-5-en-16-one 9 3β,17β-dihydroxy-androst-4-en 103β,-methylcarbonate-androst-5-en-7,17-dione 113β,17β-dihydroxy-androst-5-en-11-one 133β,17β-diacetoxy-androst-5-ene-7α,17β-diol 143β,17β-diacetoxy-androst-5-ene-7-one 153β-methoxy-17β-hydroxy-androst-5-ene-7-one 163β-methoxy-androst-5-ene-?,17β-diol 1717β-methoxy-androst-3,5-diene-7-one 18 17-methyl-marrianolic acid 1917β-hydroxy-androst-3,5-diene-7-one 21 5α-androstane-3α,17β-diol 227-oxo-androstene-3β,17β-diol

EXAMPLE 2 Induction of AR-Mediated Transcriptional Activity

Steroid compounds were screened for their ability to induce ARtranscriptional activity in the AR-negative PC-3 cell line. The resultsof the CAT assay were obtained by transient co-transfection of ARplasmid and a reporter plasmid (MMTVCAT) containing the CAT gene linkedto the androgen response element (ARE). After transfection, the cellswere treated with various DHEA derivatives at 1000, 10, and 0.1 nM. Asshown in FIG. 1, compounds 0, 4, 5, 6, 8, 10, 13, 15, 16, 18, and 22 hadlittle androgenic activity but they did induce a low level ofAR-mediated CAT gene transactivation. AED (compound 21) had about thesame capacity as DHT to stimulate AR-mediated CAT gene transcription.

EXAMPLE 3 Identification of Anti-Adiol Activity of Steroids with LowAndrogenic Effects

Several compounds were screened for their capacity to modulate AED'seffects on AR-mediated activation of gene transcription in PC-3 cells.The chemical structures of compounds 4, 6, 8 and 10 are shown in FIG.2A. The PC-3 cells were co-transfected with pSG5 and the MMTV-CATreporter vector in the presence of 50 nM AED and each compound at aconcentration of 10, 100, or 1000 nM. As shown in FIG. 2B, compounds 4,6, 8 and 10 antagonized AED-mediated AR transcriptional activity. Atconcentrations of 0.1 μM and 1 μM, compounds 4 and 6 suppressed theAED-induced AR transactivation to less than 30%. Compounds 0, 5, 13, 15,18 and 22 show either activation of AED-mediated AR transcriptionalactivity or they have no effect.

EXAMPLE 4 Identification of Anti-DHT Effects of Steroids

Compounds 4, 6, 8 and 10 were examined to determine whether these AEDantagonists had the ability to repress DHT-induced AR transactivation.PC-3 cells were co-transfected with pSG5 and the MMTV-CAT reporterplasmid in the presence of 1 nM DHT and each compound at 10, 100, or1000 nM. Compound 4 repressed the DHT-induced AR transactivation to lessthan 40% at 1 μM (FIG. 3).

EXAMPLE 5 Suppression of the AED-Induced AR Transcriptional Activity inthe Presence of HF

To mimic the in vivo condition of total androgen blockage in prostatecancer patients, compounds 4, 6, 8 and 10 were examined for theircapacity to antagonize AED-induced AR transactivation in the presence ofHF. In the presence of 1 μM HF, 50 nM AED, and each compound at 0.01,0.1 or 1 μM, PC-3 cells were transiently transfected with pSG5 and theMMTV-CAT reporter plasmid. As shown in FIG. 4, HF suppressedAED-mediated AR transcription activity by about 40%. The compoundstested decreased AED-mediated AR transcription activity by about 75%.

EXAMPLE 6 Steroid Hormone Specificity of DHEA Metabolites (No. 4, 6, 8,& 10)

The estrogen receptor (ER)-positive MCF-7 cell line was transfected witha CAT reporter plasmid containing an estrogen response element linked tothe CAT gene. PC-3 cells were transfected with MMTV-CAT reporter andprogesterone receptor (PR) or glucocorticoid receptor (GR) to test thesteroid hormone specificity of compounds 4, 6, 8 and 10. All 4 compoundshave some estrogenic activity and only compound 4, which has a17β-ethynyl group, shows some weak PR activity. None of these fourcompounds showed any GR activity.

REFERENCES

The following citations describe various aspects of prostate cancer andrelated subject matter. 1. Landis, S. H., Murray, T., Bolden, S. &Wingo, P. A. (1999) Canadian Cancer J. Clin. 49:8-31; 2. Garnick, M. B.(1997) Urology 49:5-15; 3. Gaddipati, J. P., McLeod, D. G., Heidenberg,H. B., Sesterhenn, I. A., Finger, M. J., Moul, J. W. & Srivastava, S.(1994) Cancer Res. 54:2861-2864; 4. Miyamoto, H., Yeh, S., Lardy, H.,Messing, E. & Chang, C, (1998) Proc. Nad. Acad. Sci. USA 95:11083-11088;5. Adams, J. B. (1985) Mol. Cell. Endocrinol. 41:1-17; 6. Yeh, S. &Chang, C. (1996) Proc. Natl. Acad. Sci. USA 93:5517-5521; 7. Yeh, S.,Miyamoto, H., Shima, H. & Chang, C. (1998) Proc. Natl. Acad. Sci. USA95:5527-5532; 8. Kang, H.-Y., Yeh, S., Fujimoto, N., & Chang, C. (1999)J. Biol. Chem. 274:8570-8576; 9. Fujimoto, N., Yeh, S., Kang, H.-Y.,Inui, S., Chang, H.-C., Mizokami, A., & Chang, C. (1999) J. Biol. Chem.274:8316-8321; 10. Yeh, S., Miyamoto, H., Nishimura, K., Kang, H.,Ludlow, J., Hsiao, P., Wang, C., Su, C., & Chang, C. (1998) Biochem.Biophys. Res. Commun. 248:361-367; 11. Hslao, P-W, Lin, D-L., Nakao, R.& Chang, C, (1999) J. Biol. Chem. 274:20229-20234; 12. Hsiao, P.-W. &Chang, C. (1999) J. Biol. Chem. 274:22373-22379; 13. Belanger, A.,Brochu, M. & Cliche, J. (1986) J. Clin. Endocrinol. Metab. 62:812-815;14. Hirschmann, H., de Courcy, C., Levy, R. P. & Miller, K. L. (1960) J.Biol. Chem. 235:PC48-PC49; 15. Kirschner, M. A., Sinhamahapatra, S.,Zucker, 1. R., Lorlaux, L. & Nieschiag, E. (1973) J. Clin. Endocrinol.Metab. 37:183-189; 16. Bonney, R. C., Scanlon, M. J., Jones, D. L.,Beranek, P. A., Reed, M. J. & James, V. H (1984) J. Steroid Biochem.20:1353-1355; 17. Mills, 1. H. (1967) Proc. Royal Soc. Med. 60:905-906;18. Labrie, F., Dupont, A., Giguere, M., Borsanyi, J. P., Lacourclere,Y., Monfette, G., Emond, J. & Bergeron, N. (1988) Br. J. Urol.61:341-346; 19. Lardy, H., Kneer, N., Wei, Y., Partridge, B., & Marwah,P. (1998) Steroids 63:158-165; 20. Reich, I., Lardy, H., Wei. Y.,Marwah, P., Kneer, N., Powell, D., & Reich, H. J. (1998) Steroids63:542-553; 21. Kelly, W. K., Slovin, S. & Scher, H. 1. (1997) Urol.Clin. North Am. 24:421-431; 22. Veldscholte, J., Ris-Stalpers, C.,Kuiper, G. G. J. M., Jenster, G., Berrevoets, C., Claassen, E., vanRooij, H. C., Trapman, J., Brinkmann, A. O. & Mulder, E. (1990) Biochem.Biophys. Res. Commun. 173:534-540; 23. Suzuki, H., Akakura, K., Komiya,A., Aida, S., Akimoto, S. & Shimazaki, J. (1996) Prostate 29:153-158;24. Kuil, C. W., Berrevoets, C. A. & Mulder E. (1995) J. Biol. Chem.270:27569-27576; 25. Wong, C., Kelce, W. R., Sar, M. & Wilson, E. M.(1995) J. Biol. Chem. 70:19998-20003; 26. Yeh, S., Miyamoto, H. & Chang,C. (1997) Lancet 349:852-853; 27. Miyamoto, H., Yeh, S., Wilding, G. &Chang, C. (1998) Proc. Natl. Acad. Sci. USA 95:7379-7984; 28. Chang, H.C, et al., Proc. Nat'l. Acad. Sci. USA 96:11173-11177 1999.

What is claimed is:
 1. A compound having the structure

wherein R⁶ is —OH or —O—C(O)—CH₃; R¹⁷ is —OH or —O—C(O)—CH₃; R¹⁸ is —OHor —O—C(O)—CH₃; R¹⁹ is —H; and R²⁴ is —CH₃ or —CH₂OH, wherein thecompound is a purified and isolated solid.
 2. The compound of claim 1wherein the compound has the structure


3. The compound of claim 2 wherein the solid is a powder or granules. 4.The compound of claim 2 wherein the compound has the structure


5. The compound of claim 4 wherein the solid is a powder or granules. 6.The compound of claim 1 wherein the compound has the structure


7. The compound of claim 6 wherein the solid is a powder or granules. 8.A compound having the structure

wherein R⁶ is —OH or —O—C(O)—CH₃; R¹⁶ is —OH or —O—C(O)—CH₃; R¹⁸ is —OHor —O—C(O)—CH₃; R¹⁹ is —CCH; and R²⁴ is —CH₃.
 9. The compound of claim 8wherein the compound has the structure


10. The compound of claim 9 wherein the compound is a solid.
 11. Thecompound of claim 8 wherein the compound has the structure


12. The compound of claim 11 wherein the compound is a solid.
 13. Thecompound of claim 8 wherein the compound has the structure


14. The compound of claim 8 wherein the compound has the structure


15. A pharmaceutical formulation comprising one or more excipients and acompound having the structure

wherein R⁶ is —OH or —O—C(O)—CH₃; R¹⁶ is —OH or —O—C(O)—CH₃; R¹⁸ is —OHor —O—C(O)—CH₃; R¹⁹ is —CCH; and R²⁴ is —CH₃.
 16. The pharmaceuticalformulation of claim 15 wherein the pharmaceutical formulation is aformulation for oral, parenteral, aerosol or topical administration. 17.The pharmaceutical formulation of claim 15 wherein the compound has thestructure


18. The pharmaceutical formulation of claim 15 wherein thepharmaceutical formulation is a formulation for oral, parenteral,aerosol or topical administration.
 19. The pharmaceutical formulation ofclaim 15 wherein the compound has the structure


20. The pharmaceutical formulation of claim 19 wherein thepharmaceutical formulation is a formulation for oral, parenteral,aerosol or topical administration.
 21. The pharmaceutical formulation ofclaim 15 wherein the compound has the structure


22. The pharmaceutical formulation of claim 21 wherein thepharmaceutical formulation is a formulation for oral, parenteral,aerosol or topical administration.
 23. The pharmaceutical formulation ofclaim 15 wherein the compound has the structure


24. The pharmaceutical formulation of claim 23 wherein thepharmaceutical formulation is a formulation for oral, parenteral,aerosol or topical administration.